Olanzapine analogs and methods of use thereof

ABSTRACT

The invention relates to novel compounds and methods of using them for modulating sleep.

RELATED APPLICATIONS

This non-provisional patent application claims priority under 35 U.S.C.§119(e) to U.S. Provisional Patent Application Ser. No. 60/707,368,filed Aug. 11, 2005, which is herein incorporated by reference in itsentirety.

FIELD OF THE INVENTION

The invention relates to methods for treating sleep disorders andcompositions useful in such methods.

BACKGROUND OF THE INVENTION

Difficulty falling asleep or remaining asleep is a significant medicalissue that arises for a variety of reasons. Sometimes, these problemsarise from endogenous conditions such as sleep apnea or insomnia. Othertimes, these problems arise from exogenous stresses such as thedisruptive effect of shift work schedules and “jet lag.” Whether causedby an endogenous or exogenous source, difficulty falling asleep orremaining asleep can result in problem sleepiness, which impairs thehealth, quality of life and safety of those affected.

Existing pharmaceutical treatments for inducing sleep include sedativesor hypnotics, such as benzodiazepine and barbiturate derivatives. Thesetreatments have numerous drawbacks, including rebound insomnia, delayedonset of desired sedative effects, persistence of sedative effects afterthe desired sleep period, and side effects due to nonspecific activitysuch as psychomotor and memory deficits, myorelaxation, and disturbedsleep architecture, including REM sleep inhibition. Additionally,sedatives and hypnotics can be habit forming, can lose theireffectiveness after extended use and may be metabolized more slowly bysome people.

Consequently, physicians often recommend or prescribe antihistamines asa milder treatment for sleep disorders when hypnotics are lessappropriate. However, many antihistamines produce a number of sideeffects, such as prolongation of the QT interval in a subject'selectrocardiogram, as well as central nervous system (CNS) side effects,including decreased muscle tone and drooping eyelids. Finally, suchcompounds can bind to muscarinic receptors, which leads toanti-cholinergic side effects such as blurred vision, dry mouth,constipation, urinary problems, dizziness and anxiety.

As a result, there is a need for sleep disorder treatments with reducedside effects. Additionally, while known sleep-inducing compounds areeffective for treating sleep-onset insomnia, i.e., a subject'sdifficulty in falling asleep, there are no drugs currently indicated fortreating sleep maintenance insomnia, i.e., maintaining a subject's sleepthroughout a normal sleep period after falling asleep. Therefore, thereis also a need for improved pharmaceutical treatments for maintainingsleep in subjects in need of such treatment.

SUMMARY OF THE INVENTION

The present invention relates to olanzapine analogs and their use tomodulate sleep. Olanzapine (ZYPREXA®) is a psychotropic agent thatbelongs to the thienobenzodiazepine class and is approved for thetreatment of schizophrenia, for maintenance of treatment response inschizophrenia, for treatment of acute mania associated with bipolar Idisorder in patients displaying a manic or mixed episode as monotherapyand in combination therapy with both divalproex and lithium, as well asmaintenance treatment in bipolar disorder. The chemical designation is2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine.Olanzapine has the following structure:

In one aspect, the invention relates to a method of modulating sleep ina subject by administering to the subject a therapeutically effectiveamount of a compound of Formula I:

or a pharmaceutically effective salt thereof, wherein: m, n, o, p, and qare, independently, an integer 0, 1, 2, 3, 4, 5, or 6; A and B are,independently, O, S, NR₇, or C(R₈)₂; X and Y are, independently, absent,O, S, C(O), SO or SO₂; R₁, R₂, R₃, R₄, R₅, R₆ R₇, and R₈ are,independently, H, F, Cl, Br, OH, CH₃, C₂, C₃, C₄, C₅, C₆ straight chainalkyl, C₃, C₄, C₅, C₆ branched alkyl, C₃, C₄, C₅, C₆, C₇ cycloalkyl, C₃,C₄, C₅, C₆, C₇ heterocyclyl, OCH₃, OCF₃, CH₂OCH₃, CH₂CH₂OCH₃,CH₂OCH₂CH₃, C₁, C₂, C₃, C₄, C₅, C₆ hydroxyalkyl, or C₁, C₂, C₃, C₄, C₅,C₆ alkoxy; any hydrogen in the CH₂ groups in the linker is optionallysubstituted with H, F, Cl, OH, Br, CF₃, CH₃, C₂, C₃, C₄, C₅, C₆ straightchain alkyl, C₃, C₄, C₅, C₆ branched alkyl, C₃, C₄, C₅, C₆, C₇cycloalkyl, C₃, C₄, C₅, C₆, C₇ heterocyclyl, OCH₃, OCF₃, CH₂OCH₃,CH₂CH₂OCH₃, CH₂OCH₂CH₃, C₁, C₂, C₃, C₄, C₅, C₆ hydroxyalkyl; or C₁, C₂,C₃, C₄, C₅, C₆ alkoxy; R₉, R₁₀, R₁₁, and R₁₂ are, independently, H, C₁,C₂, C₃, C₄, C₅ straight chain alkyl, C₂, C₃, C₄, C₅, C₆ branched alkyl,or R₉ and R₁₀ together with the carbon to which they are attached areabsent or are connected to form a spiro ring of size 3, 4, 5, 6, or 7,or R₁₁ and R₁₂ together with the carbon to which they are attached areconnected to form a spiro ring of size 3, 4, 5, 6, or 7, or substituentson two different carbon atoms are connected to form a ring of size 3, 4,5, 6, or 7; Z is selected from CO₂H, CO₂R₁₃, where R₁₃ is C₁, C₂, C₃,C₄, C₅, C₆ alkyl; CONR₁₄R₁₅, where R₁₄ and R₁₅ are, independently,hydrogen or lower alkyl; CONHS(O)₂-alkyl, CONHS(O)₂-cycloalkyl,CONHS(O)₂-heteroalkyl, CONHS(O)₂-aryl, CONHS(O)₂-heteroaryl,S(O)₂NHCO-alkyl, S(O)₂NHCO-cycloalkyl, S(O)₂NHCO-heteroalkyl,S(O)₂NHCO-aryl, S(O)₂NHCO-heteroaryl, CONHS(O)₂N-alkyl,CONHS(O)₂N-cycloalkyl, CONHS(O)₂N-heteroalkyl, CONHS(O)₂N-aryl,CONHS(O)₂N-heteroaryl, SO₃H, SO₂H, S(O)NHCO-alkyl, S(O)NHCO-aryl,S(O)NHCO-heteroaryl, P(O)(OH)₂, P(O)OH,

provided that when m is zero, X is absent.

In one embodiment, Z is a sulfonamide. Typical sulfonamides include acylsulfonamides. For example, Z can have the formula

where W is a substituent chosen as needed to modulate the effects of thepolar surface area of the Z moiety such that the desired level of oralabsorption, CNS penetration, and rate of excretion into urine or bile isobtained. Examples of useful W substituents for this purpose include analkyl group (optionally containing a double or triple bond), acycloalkyl group (optionally containing a double bond), a heterocyclylgroup, an aryl group or a heteroaryl group, both optionally substituted,such as those shown below:

(where V is one or more side chains selected to modulate the pKa of theacylsulfonamide moiety, or to affect the physical or metabolicproperties of the compound. Examples of V side chains include halogenssuch as F, Cl, or Br; Cl, C₂, C₃, C₄, C₅, C₆ alkoxy groups such as OCH₃or OCH₂CH₃; C₁, C₂, C₃, C₄, C₅, C₆ alkyl or C₃, C₄, C₅, C₆, C₇, C₈cycloalkyl groups such as CH₃ or CF₃, cyclopropyl; heteroatomsubstituted C₁, C₂, C₃, C₄, C₅, C₆ alkyl or C₃, C₄, C₅, C₆, C₇, C₈cycloalkyl, such as CH₂OCH₃, or CH₂OCH₂CH₃; electron withdrawing groupssuch as CN, a ketone, an amide, or a sulfone.

(and pyridyl isomers),

(and pyrimidine isomers), and

In one embodiment, Z is a sulfamide. Typical sulfamides include acylsulfamides. For example, Z can have the formula

where R_(a) and R_(b) are, independently, for example an alkyl group, acycloalkyl group, a heterocyclyl group, an aryl group or a heteroarylgroup, optionally substituted. Examples include the following:

(where V is a halogen such as F, Cl, or Br; C₁-C₆ alkoxy such as OCH₃ orOCH₂CH₃; C₁, C₂, C₃, C₄, C₅, C₆ alkyl or C₃, C₄, C₅, C₆, C₇, C₈cycloalkyl such as CH₃ or CF₃, cyclopropyl; heteroatom substituted C₁,C₂, C₃, C₄, C₅, C₆ alkyl or C₃, C₄, C₅, C₆, C₇, C₈ cycloalkyl, such asCH₂OCH₃, or CH₂OCH₂CH₃; an electron withdrawing group such as CN, aketone, an amide, or a sulfone),

(and pyridyl isomers),

(and pyrimidine isomers).

In one embodiment, the compounds of Formula I for use in the methods ofthe invention have one or more of the following characteristics: aninhibition constant (K_(i)) with regard to H1 receptor binding of lessthan 500 nM; a K_(i) with regard to off target binding to an off targetselected from M1, M2, M3, D1, D2, α1 and α2 that is greater than 1,000nm and/or more than 10 times greater than the K_(i) with regard to theH1 receptor; a nonREM peak time value that is greater than 55% nonREMsleep per hour by the third hour after the compound is administered to asubject; a cumulative total increase in nonREM sleep of not less than 20minutes for compound doses that produce maximum sleep consolidation; alongest sleep bout that is greater than 13 minutes in duration; netlongest sleep bout post treatment is greater than or equal to 3 minuteswhen adjusted using a baseline value obtained at least 24 hours prior toadministration of the compound to a subject; an average sleep bout thatis greater than 5 minutes at absolute peak; administration of thecompound to a subject does not produce appreciable amounts of reboundinsomnia; administration of the compound to a subject does notappreciably inhibit REM sleep; and administration of the compound to asubject does not disproportionately inhibit locomotor activity relativeto the normal effects of sleep.

In another embodiment, the compound of Formula I for use in the methodsof the invention has one or more of the following characteristics: aninhibition constant (K_(i)) with regard to H1 receptor binding of lessthan 300 nM; a K_(i) with regard to off target binding to an off targetselected from M1, M2, M3, D1, D2, α1 and α2 that is greater than 1 μm; anonREM peak time value that is greater than 55% nonREM sleep per hour bythe third hour after the compound is administered to a subject; acumulative total increase in nonREM sleep of not less than 20 minutesfor compound doses that produce maximum sleep consolidation; a longestsleep bout that is greater than 13 minutes in duration; net longestsleep bout post treatment is greater than or equal to 3 minutes whenadjusted using a baseline value obtained at least 24 hours prior toadministration of the compound to a subject; an average sleep bout thatis greater than 5 minutes at absolute peak; administration of thecompound to a subject does not produce appreciable amounts of reboundinsomnia; administration of the compound to a subject does notappreciably inhibit REM sleep; and administration of the compound to asubject does not disproportionately inhibit locomotor activity relativeto the normal effects of sleep.

In another embodiment, the compound of Formula I for use in the methodsof the invention has one or more of the following characteristics: aninhibition constant (K_(i)) with regard to H1 receptor binding of lessthan 150 nM; a K_(i) with regard to off target binding to an off targetselected from M1, M2, and M3, that is greater than 10 μM; a nonREM peaktime value that is greater than 55% nonREM sleep per hour by the thirdhour after the compound is administered to a subject; a cumulative totalincrease in nonREM sleep not less than 20 minutes for compound dosesthat produce maximum sleep consolidation; a longest sleep bout that isgreater than 17 minutes in duration; net longest sleep bout posttreatment is greater than or equal to 5 minutes when adjusted using abaseline value obtained at least 24 hours prior to administration of thecompound to a subject; an average sleep bout that is greater than 6minutes at absolute peak; administration of the compound to a subjectdoes not produce appreciable amounts of rebound insomnia; administrationof the compound to a subject does not appreciably inhibit REM sleep; andadministration of the compound to a subject does not disproportionatelyinhibit locomotor activity or motor tone relative to the normal effectsof sleep.

In one embodiment, in the compound used in the method of the invention,R6 is not hydrogen or halogen. In another embodiment, R₆ is methyl,ethyl, isopropyl, methoxy, methoxymethylene (CH₂OCH₃), or hydroxy. Inanother embodiment, in the compound used in the method of the invention,R₆ is methyl, methoxy, methoxymethylene, fluoro, chloro, bromo orhydroxy.

In another embodiment, in the compound of Formula I used in the methodof the invention, R₁, R₂, R₃, R₄, and R₅ are each hydrogen.

In another embodiment, in the compound of Formula I used in the methodof the invention, A is NR₇. In another embodiment, in the compound ofFormula I used in the method of the invention, A is NR₇ and R₇ isselected from H and CH₃. In one embodiment, R₇ is H.

In another embodiment, in the compound of Formula I used in the methodof the invention, B is O or S. In another embodiment, in the compound ofFormula I used in the method of the invention, B is S.

In another embodiment, in the compound of Formula I used in the methodof the invention, at least one of R₁, R₂, R₃, R₄, R₅, R₆ is anon-hydrogen substituent and the remaining R₁, R₂, R₃, R₄, R₅, R₆ arehydrogen. In another embodiment, in the compound used in the method ofthe invention, the at least one non-hydrogen R₁, R₂, R₃, R₄, R₅, R₆ isindependently methyl, ethyl, isopropyl, methoxy, methoxymethylene,fluoro, chloro, bromo or hydroxy.

In another embodiment, in the compound of Formula I used in the methodof the invention, at least two of R₁, R₂, R₃, R₄, R₅, R₆ arenon-hydrogen substituents, and the remaining R₁, R₂, R₃, R₄, R₅, R₆ arehydrogen. In another embodiment, in the compound used in the method ofthe invention, the at least 2 non-hydrogen R₁, R₂, R₃, R₄, R₅, R₆ areindependently methyl, methoxy, methoxymethylene, fluoro, chloro, bromoor hydroxy.

In another embodiment, in the compound of Formula I used in the methodof the invention, at least three of R₁, R₂, R₃, R₄, R₅, R₆ arenon-hydrogen substituents, and the remaining R₁, R₂, R₃, R₄, R₅, R₆ arehydrogen. In another embodiment, in the compound used in the method ofthe invention, the at least 3 non-hydrogen R₁, R₂, R₃, R₄, R₅, R₆ areindependently methyl, methoxy, methoxymethylene, fluoro, chloro, bromoor hydroxy.

In another embodiment, in the compound of Formula I used in the methodof the invention, R₂ is a non-hydrogen substituent. For example, R₂ is,e.g., methyl, methoxy, methoxymethylene, fluoro, chloro, bromo orhydroxy.

In another embodiment, in the compound of Formula I used in the methodof the invention, R₃ is a non-hydrogen substituent. For example, R₃ is,e.g., methoxy, methyl, methoxymethylene, fluoro, chloro, bromo orhydroxy.

In another embodiment, in the compound of Formula I used in the methodof the invention, R₅ is a non-hydrogen substituent. For example, R₅ is,e.g., methyl, methoxy, methoxymethylene, fluoro, chloro, bromo orhydroxy.

In another embodiment, in the compound of Formula I used in the methodof the invention, R₆ is a non-hydrogen substituent. For example, R₆ is,e.g., methyl, ethyl, isopropyl, methoxy, methoxymethylene, fluoro,chloro, bromo or hydroxy.

In another embodiment, in the compound of Formula I used in the methodof the invention, R₂ and R₃ are non-hydrogen substituents. For example,R₂ and R₃ are, e.g., independently, methyl, methoxy, methoxymethylene,fluoro, chloro, bromo or hydroxy.

In another embodiment, in the compound of Formula I used in the methodof the invention, R₂ and R₆ are non-hydrogen substituents. For example,R₂ and R₆ are, e.g., independently, methyl, ethyl, isopropyl, methoxy,methoxymethylene, fluoro, chloro, bromo or hydroxy.

In another embodiment, in the compound of Formula I used in the methodof the invention, R₂ and R₅ are non-hydrogen substituents. For example,R₂ and R₅ are, e.g., independently, methyl, methoxy, methoxymethylene,fluoro, chloro, bromo or hydroxy.

In another embodiment, in the compound of Formula I used in the methodof the invention, R₃ and R₆ are non-hydrogen substituents. For example,R₃ and R₆ are, e.g., independently, methyl, methoxy, methoxymethylene,fluoro, chloro, bromo or hydroxy.

In another embodiment, in the compound of Formula I used in the methodof the invention, R₃ and R₅ are non-hydrogen substituents. For example,R₃ and R₅ are, e.g., independently, methyl, methoxy, methoxymethylene,fluoro, chloro, bromo or hydroxy.

In another embodiment, in the compound of Formula I used in the methodof the invention, R₅ and R₆ are non-hydrogen substituents. For example,R₅ and R₆ are, e.g., independently, methyl, ethyl, isopropyl, methoxy,methoxymethylene, fluoro, chloro, bromo or hydroxy.

In another embodiment, in the compound of Formula I used in the methodof the invention, R₆ is methyl or methoxy, and R₁, R₂, R₃, R₄, and R₅are hydrogen.

In another embodiment, in the compound of Formula I used in the methodof the invention, R₂ is methyl or methoxy, and R₁, and R₃, R₄, R₅, andR₆ are hydrogen.

In another embodiment, in the compound of Formula I used in the methodof the invention, R₃ is methyl or methoxy and R₁, R₂, and R₄, R₅, R₆ arehydrogen.

In another embodiment, in the compound of Formula I used in the methodof the invention, R₆ is methoxy and R₁, R₂, R₃, R₄, and R₅, arehydrogen.

In another embodiment, in the compound of Formula I used in the methodof the invention, R₅ is methyl or methoxy and R₁, R₂, R₃, R₄, and R₆,are hydrogen.

In one embodiment, in the compound of Formula I used in the method ofthe invention, at least one of R₂, R₅, and R₆ is not hydrogen. Inanother embodiment, in the compound of Formula I used in the method ofthe invention, at least one of R₂, R₅, and R₆ is fluoro, methyl, ormethoxy.

In one embodiment R₉ and R₁₀ together with the carbon to which they areattached are absent. In another embodiment, in the compound of Formula Iused in the method of the invention, R₁₁ and R₁₂ are each methyl. Inanother embodiment, in the compound used in the method of the invention,R₁₁ and R₁₂ are each ethyl. In another embodiment, in the compound usedin the method of the invention, R₁₁ and R₁₂, together with the carbon towhich they are attached, are connected to form a spiro ring of size 3,4, 5, 6, or 7. The spiro ring is, e.g., a cyclopropyl ring.

In one embodiment, in the compound of Formula I used in the method ofthe invention, q is zero. In another embodiment, q is zero, and R₉ andR₁₀ together with the carbon to which they are attached are absent. Inanother embodiment, q is zero, R₉ and R₁₀ together with the carbon towhich they are attached are absent, X and Y are absent. In anotherembodiment, q is zero, R₉ and R₁₀ together with the carbon to which theyare attached are absent, X and Y are absent, and the sum of m, n, o, andp is 2 or 3.

In another embodiment, the compound of Formula I used in the method ofthe invention, is selected from Compounds 1-106. For example, thecompound used in the methods of the invention is Compound 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42,43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60,61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78,79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96,97, 98, 99, 100, 101, 102, 103, 104, 105, or 106. In another embodiment,the compound used in the method of the invention is Compound 46.

In one embodiment, the method of the invention is used to modulate sleepby administering a compound of Formula I, for example the method is usedto decrease the time to sleep onset, increase the average sleep boutlength, and/or increase the maximum sleep bout length. In anotherembodiment, the method of the invention is used to treat a sleepdisorder by administering a compound of Formula I. The sleep disorderis, for example, circadian rhythm abnormality, insomnia, parasomnia(such as, e.g., somnambulism, pavor nocturnus, REM sleep behaviordisorder, sleep bruxism and sleep enuresis), a sleep apnea disorder,such as, for example, central sleep apnea, obstructive sleep apnea andmixed sleep apnea, sleep apnea syndrome, narcolepsy or hypersomnia.

In one embodiment, the method of the invention is used to treatcircadian rhythm abnormality. In another embodiment, the method of theinvention is used to treat insomnia including, for example, extrinsicinsomnia, psychophysiologic insomnia, altitude insomnia, restless legsyndrome, periodic limb movement disorder, medication-dependentinsomnia, drug-dependent insomnia, alcohol-dependent insomnia andinsomnia associated with mental disorders. In another embodiment, themethod of the invention is used to treat sleep apnea. In anotherembodiment, the method of the invention is used to treat narcolepsy. Inanother embodiment, the method of the invention is used to treathypersomnia.

In one embodiment, in the method of the invention, the compound ofFormula I, or pharmaceutically acceptable salt thereof, is administeredas a pharmaceutical composition that includes a pharmaceuticallyacceptable excipient.

In another embodiment, in the method of the invention, the compound ofFormula I, or pharmaceutically acceptable salt thereof, isco-administered with one or more additional therapies.

In another embodiment, the subject treated by the method of theinvention is selected from humans, companion animals, farm animals,laboratory animals and wild animals. In one embodiment, the subject is ahuman.

In another aspect, the invention relates to a method of modulating sleepin a subject by administering to the subject a therapeutically effectiveamount of a compound of Formula II:

or a pharmaceutically effective salt thereof, wherein: m, n, and o are,independently, 0, 1, 2, 3, 4, 5, or 6, X is absent, O, S, C(O), SO orSO₂; R₂, R₃, R₅, and R₆ are, independently, selected from H, F, Cl, Br,OH, CF₃, CH₃, CH₂CH₃, CH(CH₃)₂, cyclopropyl, OCH₃, OCF₃, CH₂OCH₃ andCH₂OCH₂CH₃; R₉, and R₁₀, are, independently, H, C₁, C₂, C₃, C₄, C₅straight chain alkyl, C₂, C₃, C₄, C₅, C₆ branched alkyl, or R₉ and R₁₀together with the carbon to which they are attached, are connected toform a spiro ring of size 3, 4, 5, 6, or 7; Z is COOH, COOR₁₃, where R₁₃is C₁, C₂, C₃, C₄, C₅, C₆ alkyl, CONHS(O)₂-alkyl, CONHS(O)₂-heteroalkyl,CONHS(O)₂-aryl, CONHS(O)₂-heteroaryl, S(O)₂NHCO-alkyl,S(O)₂NHCO-heteroalkyl, S(O)₂NHCO-aryl, S(O)₂NHCO-heteroaryl,CONHS(O)₂N-alkyl; CONHS(O)₂N-heteroalkyl; CONHS(O)₂N-aryl;CONHS(O)₂N-heteroaryl; or tetrazole, provided that when m is zero, X isabsent.

In one embodiment, the compounds of Formula II for use in the methods ofthe invention have one or more of the following characteristics: aninhibition constant (K_(i)) with regard to H1 receptor binding of lessthan 500 nM; a K_(i) with regard to off target binding to an off targetselected from M1, M2, M3, D1, D2, α1 and α2 that is greater than 1,000nm and/or more than 10 times greater than the K_(i) with regard to theH1 receptor; a nonREM peak time value that is greater than 55% nonREMsleep per hour by the third hour after the compound is administered to asubject; a cumulative total increase in nonREM sleep of not less than 20minutes for compound doses that produce maximum sleep consolidation; alongest sleep bout that is greater than 13 minutes in duration; netlongest sleep bout post treatment is greater than or equal to 3 minuteswhen adjusted using a baseline value obtained at least 24 hours prior toadministration of the compound to a subject; an average sleep bout thatis greater than 5 minutes at absolute peak; administration of thecompound to a subject does not produce appreciable amounts of reboundinsomnia; administration of the compound to a subject does notappreciably inhibit REM sleep; and administration of the compound to asubject does not disproportionately inhibit locomotor activity relativeto the normal effects of sleep.

In another embodiment, the compound of Formula II for use in the methodsof the invention has one or more of the following characteristics: aninhibition constant (K_(i)) with regard to H1 receptor binding of lessthan 300 nM; a K_(i) with regard to off target binding to an off targetselected from M1, M2, M3, D1, D2, α1 and α2 that is greater than 1 μm; anonREM peak time value that is greater than 55% nonREM sleep per hour bythe third hour after the compound is administered to a subject; acumulative total increase in nonREM sleep of not less than 20 minutesfor compound doses that produce maximum sleep consolidation; a longestsleep bout that is greater than 13 minutes in duration; net longestsleep bout post treatment is greater than or equal to 3 minutes whenadjusted using a baseline value obtained at least 24 hours prior toadministration of the compound to a subject; an average sleep bout thatis greater than 5 minutes at absolute peak; administration of thecompound to a subject does not produce appreciable amounts of reboundinsomnia; administration of the compound to a subject does notappreciably inhibit REM sleep; and administration of the compound to asubject does not disproportionately inhibit locomotor activity relativeto the normal effects of sleep.

In another embodiment, the compound of Formula II for use in the methodsof the invention has one or more of the following characteristics: aninhibition constant (K_(i)) with regard to H1 receptor binding of lessthan 150 nM; a K_(i) with regard to off target binding to an off targetselected from M1, M2, and M3, that is greater than 10 μM; a nonREM peaktime value that is greater than 55% nonREM sleep per hour by the thirdhour after the compound is administered to a subject; a cumulative totalincrease in nonREM sleep not less than 20 minutes for compound dosesthat produce maximum sleep consolidation; a longest sleep bout that isgreater than 17 minutes in duration; net longest sleep bout posttreatment is greater than or equal to 5 minutes when adjusted using abaseline value obtained at least 24 hours prior to administration of thecompound to a subject; an average sleep bout that is greater than 6minutes at absolute peak; administration of the compound to a subjectdoes not produce appreciable amounts of rebound insomnia; administrationof the compound to a subject does not appreciably inhibit REM sleep; andadministration of the compound to a subject does not disproportionatelyinhibit locomotor activity or motor tone relative to the normal effectsof sleep.

In one embodiment, in the compound of Formula II used in the method ofthe invention, R₆ is not methyl. In one embodiment, in the compound ofFormula II used in the method of the invention, R₆ is methyl. In anotherembodiment, in the compound of Formula II used in the method of theinvention, R₆ is methoxy, methoxymethylene, bromo, fluoro, methyl,ethyl, isopropyl, or hydroxy.

In another embodiment, in the compound of Formula II used in the methodof the invention, R₂-R₃ and R₅ are each hydrogen. In another embodiment,in the compound of Formula II used in the method of the invention, R₂-R₃and R₅-R₆ are independently hydrogen, methyl, ethyl, isopropyl, methoxy,methoxymethylene, fluoro, chloro, bromo or hydroxy. In anotherembodiment, in the compound of Formula II used in the method of theinvention, R₂ is a non-hydrogen substituent. In another embodiment, inthe compound of Formula II used in the method of the invention, R₃ is anon-hydrogen substituent. In another embodiment, in the compound ofFormula II used in the method of the invention, R₅ is a non-hydrogensubstituent. In another embodiment, in the compound of Formula II usedin the method of the invention, R₆ is a non-hydrogen substituent. Inanother embodiment, in the compound of Formula II used in the method ofthe invention, R₂ and R₃ are non-hydrogen substituents. In anotherembodiment, in the compound of Formula II used in the method of theinvention, R₂ and R₅ are non-hydrogen substituents. In anotherembodiment, in the compound of Formula II used in the method of theinvention, R₂ and R₆ are non-hydrogen substituents. In anotherembodiment, in the compound of Formula II used in the method of theinvention, R₃ and R₅ are non-hydrogen substituents. In anotherembodiment, in the compound of Formula II used in the method of theinvention, R₃ and R₆ are non-hydrogen substituents. In anotherembodiment, in the compound of Formula II used in the method of theinvention, R₅ and R₆ are non-hydrogen substituents.

In another embodiment, in the compound of Formula II used in the methodof the invention, R₆ is methyl or methoxy, and R₂, R₃ and R₅ arehydrogen. In another embodiment, in the compound of Formula II used inthe method of the invention, R₂ is methyl or methoxy, and R₃, R₅ and R₆are hydrogen. In another embodiment, in the compound of Formula II usedin the method of the invention, R₃ is methyl and R₂, R₅ and R₆ arehydrogen. In another embodiment, in the compound of Formula II used inthe method of the invention, wherein R₅ is methoxy and R₂, R₃ and R₆ arehydrogen. In another embodiment, in the compound of Formula II used inthe method of the invention, R₉ and R₁₀ are each methyl. In anotherembodiment, in the compound of Formula II used in the method of theinvention, R₉ and R₁₀ are each ethyl. In another embodiment, in thecompound of Formula II used in the method of the invention, R₉ and R₁₀,together with the carbon to which they are attached, are connected toform a spiro ring of size 3, 4, 5, 6, or 7. For example, the spiro ringis, e.g., a cyclopropyl ring.

In one embodiment, in the compound of Formula II used in the method ofthe invention, o is zero. In another embodiment, o is zero, and X isabsent. In another embodiment, o is zero, X is absent, and the sum of mand n is 2 or 3.

In one embodiment, the method of the invention is used to modulate sleepby administering a compound of Formula II, for example the method isused to decrease the time to sleep onset, increase the average sleepbout length, and/or increase the maximum sleep bout length. In anotherembodiment, the method of the invention is used to treat a sleepdisorder by administering a compound of Formula II. The sleep disorderis, for example, circadian rhythm abnormality, insomnia, parasomnia,sleep apnea syndrome, narcolepsy or hypersomnia.

In another aspect, the invention relates to a method of modulating sleepin a subject by administering to the subject a therapeutically effectiveamount of a compound of Formula III:

or a pharmaceutically effective salt thereof, wherein: m and n are,independently, 0, 1, 2, 3, or 4, X is absent, O, S, C(O), SO or SO₂; R₂,R₃, R₅, and R₆ are, independently, selected from H, F, Cl, Br, OH, CF₃,CH₃, CH₂CH₃, CH(CH₃)₂, OCH₃, CH₂OCH₃, and CH₂OCH₂CH₃; R₉, and R₁₀, are,independently, H, C₁, C₂, C₃, C₄, C₅ straight chain alkyl; C₂, C₃, C₄,C₅, C₆ branched alkyl, or R₉, and R₁₀, together with the carbon to whichthey are attached, are connected to form a spiro ring of size 3, 4, 5,6, or 7; Z is selected from CO₂H, CONHS(O)₂-alkyl, CONHS(O)₂-cycloalkyl,CONHS(O)₂-heteroalkyl, CONHS(O)₂-aryl, CONHS(O)₂-heteroaryl, andtetrazole; provided that when m is zero, X is absent.

In one embodiment, the compounds of Formula III for use in the methodsof the invention have one or more of the following characteristics: aninhibition constant (K_(i)) with regard to H1 receptor binding of lessthan 500 nM; a K_(i) with regard to off target binding to an off targetselected from M1, M2, M3, D1, D2, α1 and α2 that is greater than 1,000nm and/or more than 10 times greater than the K_(i) with regard to theH1 receptor; a nonREM peak time value that is greater than 55% nonREMsleep per hour by the third hour after the compound is administered to asubject; a cumulative total increase in nonREM sleep of not less than 20minutes for compound doses that produce maximum sleep consolidation; alongest sleep bout that is greater than 13 minutes in duration; netlongest sleep bout post treatment is greater than or equal to 3 minuteswhen adjusted using a baseline value obtained at least 24 hours prior toadministration of the compound to a subject; an average sleep bout thatis greater than 5 minutes at absolute peak; administration of thecompound to a subject does not produce appreciable amounts of reboundinsomnia; administration of the compound to a subject does notappreciably inhibit REM sleep; and administration of the compound to asubject does not disproportionately inhibit locomotor activity relativeto the normal effects of sleep.

In another embodiment, the compound of Formula III for use in themethods of the invention has one or more of the followingcharacteristics: an inhibition constant (K_(i)) with regard to H1receptor binding of less than 300 nM; a K_(i) with regard to off targetbinding to an off target selected from M1, M2, M3, D1, D2, α1 and α2that is greater than 1 μm; a nonREM peak time value that is greater than55% nonREM sleep per hour by the third hour after the compound isadministered to a subject; a cumulative total increase in nonREM sleepof not less than 20 minutes for compound doses that produce maximumsleep consolidation; a longest sleep bout that is greater than 13minutes in duration; net longest sleep bout post treatment is greaterthan or equal to 3 minutes when adjusted using a baseline value obtainedat least 24 hours prior to administration of the compound to a subject;an average sleep bout that is greater than 5 minutes at absolute peak;administration of the compound to a subject does not produce appreciableamounts of rebound insomnia; administration of the compound to a subjectdoes not appreciably inhibit REM sleep; and administration of thecompound to a subject does not disproportionately inhibit locomotoractivity relative to the normal effects of sleep.

In another embodiment, the compound of Formula III for use in themethods of the invention has one or more of the followingcharacteristics: an inhibition constant (K_(i)) with regard to H1receptor binding of less than 150 nM; a K_(i) with regard to off targetbinding to an off target selected from M1, M2, and M3, that is greaterthan 10 μM; a nonREM peak time value that is greater than 55% nonREMsleep per hour by the third hour after the compound is administered to asubject; a cumulative total increase in nonREM sleep not less than 20minutes for compound doses that produce maximum sleep consolidation; alongest sleep bout that is greater than 17 minutes in duration; netlongest sleep bout post treatment is greater than or equal to 5 minuteswhen adjusted using a baseline value obtained at least 24 hours prior toadministration of the compound to a subject; an average sleep bout thatis greater than 6 minutes at absolute peak; administration of thecompound to a subject does not produce appreciable amounts of reboundinsomnia; administration of the compound to a subject does notappreciably inhibit REM sleep; and administration of the compound to asubject does not disproportionately inhibit locomotor activity or motortone relative to the normal effects of sleep.

In one embodiment, in the compound of Formula III used in the method ofthe invention, R₆ is not H, F, Cl, or Br. In another embodiment, in thecompound of Formula III used in the method of the invention, R₂, R₃, andR₇ are hydrogen. In another embodiment, R₂, R₃, and R₅ are hydrogen. Inanother embodiment, in the compound of Formula III used in the method ofthe invention, R₂, R₃, R₅, and R₆ are independently H, F, Cl, Br,methyl, ethyl, isopropyl, methoxy, methoxymethylene or hydroxy. Inanother embodiment, in the compound of Formula III used in the method ofthe invention, R₆ is methoxy or methyl.

In another embodiment, in the compound of Formula III used in the methodof the invention, R₆ is methoxy or methyl, and R₂, R₃ and R₅ arehydrogen. In another embodiment, in the compound of Formula III used inthe method of the invention, R₂ is methyl or methoxy, and R₃, R₆ and R₅are hydrogen. In another embodiment, in the compound of Formula III usedin the method of the invention, R₃ is methyl and R₂, R₆ and R₅ arehydrogen. In another embodiment, in the compound of Formula II used inthe method of the invention, wherein R₅ is methoxy and R₂, R₃ and R₆ arehydrogen. In another embodiment, in the compound of Formula III used inthe method of the invention, R₉ and R₁₀ are each methyl. In anotherembodiment, in the compound of Formula III used in the method of theinvention, R₉ and R₁₀, together with the carbon to which they areattached, are connected to form a spiro ring of size 3. In oneembodiment, in the compound of Formula III used in the method of theinvention, X is absent. In another embodiment, X is absent, and the sumof m and n is 2 or 3.

In one embodiment, the method of the invention is used to modulate sleepby administering a compound of Formula III, for example the method isused to decrease the time to sleep onset, increase the average sleepbout length, and/or increase the maximum sleep bout length. In anotherembodiment, the method of the invention is used to treat a sleepdisorder by administering a compound of Formula III. The sleep disorderis, for example, circadian rhythm abnormality, insomnia, parasomnia,sleep apnea syndrome, narcolepsy or hypersomnia.

In another aspect, the invention relates to a method of modulating sleepin a subject by administering to the subject a therapeutically effectiveamount of a compound of Formula IV:

or a pharmaceutically effective salt thereof, wherein: t is 1, 2, 3, or4; R₂, R₃, R₅ and R₆ are, independently, H, F, Cl, Br, CF₃, CH₃, CH₂CH₃,CH(CH₃)₂, OH, OCH₃, CH₂OCH₃, or CH₂OCH₂CH₃; R₉-R₁₀ are H, CH₃, CH₂CH₃,or R₉ and R₁₀, together with the carbon to which they are attached areconnected to form a spiro ring of size 3, 4, 5, 6, or 7; and Z isselected from CO₂H, CONHS(O)₂-alkyl, CONHS(O)₂-cycloalkyl,CONHS(O)₂-heteroalkyl, CONHS(O)₂-aryl, CONHS(O)₂-heteroaryl, ortetrazole.

In one embodiment, the compounds of Formula IV for use in the methods ofthe invention have one or more of the following characteristics: aninhibition constant (K_(i)) with regard to H1 receptor binding of lessthan 500 nM; a K_(i) with regard to off target binding to an off targetselected from M1, M2, M3, D1, D2, α1 and α2 that is greater than 1,000nm and/or more than 10 times greater than the K_(i) with regard to theH1 receptor; a nonREM peak time value that is greater than 55% nonREMsleep per hour by the third hour after the compound is administered to asubject; a cumulative total increase in nonREM sleep of not less than 20minutes for compound doses that produce maximum sleep consolidation; alongest sleep bout that is greater than 13 minutes in duration; netlongest sleep bout post treatment is greater than or equal to 3 minuteswhen adjusted using a baseline value obtained at least 24 hours prior toadministration of the compound to a subject; an average sleep bout thatis greater than 5 minutes at absolute peak; administration of thecompound to a subject does not produce appreciable amounts of reboundinsomnia; administration of the compound to a subject does notappreciably inhibit REM sleep; and administration of the compound to asubject does not disproportionately inhibit locomotor activity relativeto the normal effects of sleep.

In another embodiment, the compound of Formula IV for use in the methodsof the invention has one or more of the following characteristics: aninhibition constant (K_(i)) with regard to H1 receptor binding of lessthan 300 nM; a K_(i) with regard to off target binding to an off targetselected from M1, M2, M3, D1, D2, α1 and α2 that is greater than 1 μm; anonREM peak time value that is greater than 55% nonREM sleep per hour bythe third hour after the compound is administered to a subject; acumulative total increase in nonREM sleep of not less than 20 minutesfor compound doses that produce maximum sleep consolidation; a longestsleep bout that is greater than 13 minutes in duration; net longestsleep bout post treatment is greater than or equal to 3 minutes whenadjusted using a baseline value obtained at least 24 hours prior toadministration of the compound to a subject; an average sleep bout thatis greater than 5 minutes at absolute peak; administration of thecompound to a subject does not produce appreciable amounts of reboundinsomnia; administration of the compound to a subject does notappreciably inhibit REM sleep; and administration of the compound to asubject does not disproportionately inhibit locomotor activity relativeto the normal effects of sleep.

In another embodiment, the compound of Formula IV for use in the methodsof the invention has one or more of the following characteristics: aninhibition constant (K_(i)) with regard to H1 receptor binding of lessthan 150 nM; a K_(i) with regard to off target binding to an off targetselected from M1, M2, and M3, that is greater than 10 μM; a nonREM peaktime value that is greater than 55% nonREM sleep per hour by the thirdhour after the compound is administered to a subject; a cumulative totalincrease in nonREM sleep not less than 20 minutes for compound dosesthat produce maximum sleep consolidation; a longest sleep bout that isgreater than 17 minutes in duration; net longest sleep bout posttreatment is greater than or equal to 5 minutes when adjusted using abaseline value obtained at least 24 hours prior to administration of thecompound to a subject; an average sleep bout that is greater than 6minutes at absolute peak; administration of the compound to a subjectdoes not produce appreciable amounts of rebound insomnia; administrationof the compound to a subject does not appreciably inhibit REM sleep; andadministration of the compound to a subject does not disproportionatelyinhibit locomotor activity or motor tone relative to the normal effectsof sleep.

In one embodiment, in the compound of Formula IV used in the method ofthe invention, t is 1 or 2. In one embodiment, the compound of FormulaIV used in the method of the invention is selected from a compound offormula IVa, IVb, IVc, IVd, and IVe.

In one embodiment, the method of the invention is used to modulate sleepby administering a compound of Formula IV, for example the method isused to decrease the time to sleep onset, increase the average sleepbout length, and/or increase the maximum sleep bout length. In anotherembodiment, the method of the invention is used to treat a sleepdisorder by administering a compound of Formula IV. The sleep disorderis, for example, circadian rhythm abnormality, insomnia, parasomnia,sleep apnea syndrome, narcolepsy or hypersomnia.

In another aspect, the invention relates to a method of modulating sleepin a subject by administering to the subject a therapeutically effectiveamount of a compound of selected from Compound 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26,27, 28, 29, 30, 31, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63,64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81,82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99,100, 101, 102, 103, 104, 105, or 106. In another aspect, the inventionrelates to a method of modulating sleep in a subject by administering tothe subject a therapeutically effective amount of Compound 46.

In another aspect, the invention relates to a compound of Formula I:

or a pharmaceutically effective salt thereof, wherein: m, n, o, p, qare, independently, an integer from 0, 1, 2, 3, 4, 5, or 6; A and B are,independently, O, S, NR₇, or C(R₈)₂; X and Y are, independently, absent,O, S, C(O), SO or SO₂; R₁, R₂, R₃, R₄, R₅, R₆ R₇, and R₈ are,independently, H, F, Cl, Br, OH, CH₃, C₂, C₃, C₄, C₅, C₆ straight chainalkyl, C₃, C₄, C₅, C₆ branched alkyl, C₃, C₄, C₅, C₆, C₇ cycloalkyl, C₃,C₄, C₅, C₆, C₇ heterocyclyl, OCH₃, OCF₃, CH₂OCH₃, CH₂CH₂OCH₃,CH₂OCH₂CH₃, C₁, C₂, C₃, C₄, C₅, C₆ hydroxyalkyl, or C₁, C₂, C₃, C₄, C₅,C₆ alkoxy; any hydrogen in the CH₂ groups in the linker is optionallysubstituted with H, F, Cl, OH, Br, CF₃, CH₃, C₂, C₃, C₄, C₅, C₆ straightchain alkyl, C₃, C₄, C₅, C₆ branched alkyl, C₃, C₄, C₅, C₆, C₇cycloalkyl, C₃, C₄, C₅, C₆, C₇ heterocyclyl, OCH₃, OCF₃, CH₂OCH₃,CH₂CH₂OCH₃, CH₂OCH₂CH₃, C₁, C₂, C₃, C₄, C₅, C₆ hydroxyalkyl; or C₁, C₂,C₃, C₄, C₅, C₆ alkoxy; R₅, R₁₀, R₁₁, and R₁₂ are, independently, H, C₁,C₂, C₃, C₄, C₅ straight chain alkyl, C₂, C₃, C₄, C₅, C₆ branched alkyl,or R₉ and R₁₀ together with the carbon to which they are attached areabsent or are connected to form a spiro ring of size 3, 4, 5, 6, or 7,or R₁₁ and R₁₂ together with the carbon to which they are attached areconnected to form a spiro ring of size 3, 4, 5, 6, or 7, or substituentson two different carbon atoms are connected to form a ring of size 3, 4,5, 6, or 7; Z is selected from CO₂H, CO₂R₁₃, where R₁₃ is C₁, C₂, C₃,C₄, C₅, C₆ alkyl, CONR₁₄R₁₅, where R₁₄ and R₁₅ are, independently,hydrogen or lower alkyl, CONHS(O)₂-alkyl, CONHS(O)₂-cycloalkyl,CONHS(O)₂-heteroalkyl, CONHS(O)₂-aryl, CONHS(O)₂-heteroaryl,S(O)₂NHCO-alkyl, S(O)₂NHCO-cycloalkyl, S(O)₂NHCO-heteroalkyl,S(O)₂NHCO-aryl, S(O)₂NHCO-heteroaryl, CONHS(O)₂N-alkyl,CONHS(O)₂N-cycloalkyl, CONHS(O)₂N-heteroalkyl, CONHS(O)₂N-aryl,CONHS(O)₂N-heteroaryl, SO₃H, SO₂H, S(O)NHCO-alkyl, S(O)NHCO-aryl,S(O)NHCO-heteroaryl, P(O)(OH)₂, P(O)OH,

provided that when m is zero, X is absent.

In one embodiment, Z is a sulfonamide. Typical sulfonamides include acylsulfonamides. For example, Z can have the formula

where W is a substituent chosen as needed to modulate the effects of thepolar surface area of the Z moiety such that the desired level of oralabsorption, CNS penetration, and rate of excretion into urine or bile isobtained. Examples of useful W substituents for this purpose include analkyl group (optionally containing a double or triple bond), acycloalkyl group (optionally containing a double bond), a heterocyclylgroup, an aryl group or a heteroaryl group, both optionally substituted,such as those shown below:

(where V is one or more side chains selected to modulate the pKa of theacylsulfonamide moiety, or to affect the physical or metabolicproperties of the compound. Examples of V side chains include halogenssuch as F, Cl, or Br; C₁, C₂, C₃, C₄, C₅, C₆ alkoxy groups such as OCH₃or OCH₂CH₃; C₁, C₂, C₃, C₄, C₅, C₆ alkyl or C₃, C₄, C₅, C₆, C₇, C₈cycloalkyl groups such as CH₃ or CF₃, cyclopropyl; heteroatomsubstituted C₁, C₂, C₃, C₄, C₅, C₆ alkyl or C₃, C₄, C₅, C₆, C₇, C₈cycloalkyl, such as CH₂OCH₃, or CH₂OCH₂CH₃; electron withdrawing groupssuch as CN, a ketone, an amide, or a sulfone.

(and pyridyl isomers),

(and pyrimidine isomers), and

In one embodiment, Z is a sulfamide. Typical sulfamides include acylsulfamides. For example, Z can have the formula

where R_(a) and R_(b) are, independently, for example an alkyl group, acycloalkyl group, a heterocyclyl group, an aryl group or a heteroarylgroup, optionally substituted. Examples include the following:

(where V is a halogen such as F, Cl, or Br; C₁, C₂, C₃, C₄, C₅, C₆alkoxy such as OCH₃ or OCH₂CH₃; C₁, C₂, C₃, C₄, C₅, C₆ alkyl or C₃, C₄,C₅, C₆, C₇, C₈ cycloalkyl such as CH₃ or CF₃, cyclopropyl; heteroatomsubstituted C₁, C₂, C₃, C₄, C₅, C₆ alkyl or C₃, C₄, C₅, C₆, C₇, C₈cycloalkyl, such as CH₂OCH₃, or CH₂OCH₂CH₃; an electron withdrawinggroup such as CN, a ketone, an amide, or a sulfone),

(and pyridyl isomers),

(and pyrimidine isomers).

In one embodiment, in the compound of Formula I, R₆ is not hydrogen orhalogen. In another embodiment, in the compound of Formula I, R₆ ismethyl, ethyl, isopropyl, methoxy, methoxymethylene, fluoro, chloro,bromo, or hydroxy.

In another embodiment, in the compound of Formula I, R₁, R₂, R₃, R₄, andR₅ are each hydrogen. In another embodiment, in the compound of FormulaI, at least one of R₁, R₂, R₃, R₄, R₅, and R₆ is a non-hydrogensubstituent and the remaining R₁, R₂, R₃, R₄, R₅, and R₆ are hydrogen.In another embodiment, the at least one non-hydrogen R₁, R₂, R₃, R₄, R₅,and R₆ is independently methyl, ethyl, isopropyl, methoxy,methoxymethylene, fluoro, chloro, bromo or hydroxy. In anotherembodiment, in the compound of Formula I, at least two of R₁, R₂, R₃,R₄, R₅, and R₆ are non-hydrogen substituents, and the remaining R₁, R₂,R₃, R₄, R₅, and R₆ are hydrogen. In another embodiment, the at least twonon-hydrogen R₁, R₂, R₃, R₄, R₅, and R₆ are independently methyl,methoxy, methoxymethylene, fluoro, chloro, bromo or hydroxy. In anotherembodiment, in the compound of Formula I, at least three of R₁, R₂, R₃,R₄, R₅, and R₆ are non-hydrogen substituents, and the remaining R₁, R₂,R₃, R₄, R₅, and R₆ are hydrogen. In another embodiment, the at leastthree non-hydrogen R₁, R₂, R₃, R₄, R₅, and R₆ are independently methyl,methoxy, methoxymethylene, fluoro, chloro, bromo or hydroxy.

In another embodiment, in the compound of Formula I used in the methodof the invention, A is NR₇. In another embodiment, in the compound ofFormula I used in the method of the invention, A is NR₇ and R₇ isselected from H and CH₃. In one embodiment, R₇ is H.

In another embodiment, in the compound of Formula I used in the methodof the invention, B is O or S. In another embodiment, in the compound ofFormula I used in the method of the invention, B is S.

In another embodiment, in the compound of Formula I, R₂ is anon-hydrogen substituent. For example, R₂ is, e.g., methyl, methoxy,methoxymethylene, fluoro, chloro, bromo or hydroxy. In anotherembodiment, in the compound of Formula I, R₃ is a non-hydrogensubstituent. For example, R₃ is, e.g., methyl, methoxy,methoxymethylene, fluoro, chloro, bromo or hydroxy. In anotherembodiment, in the compound of Formula I, R₅ is a non-hydrogensubstituent. For example, R₅ is, e.g., methyl, methoxy,methoxymethylene, fluoro, chloro, bromo or hydroxy. In anotherembodiment, in the compound of Formula I, R₆ is a non-hydrogensubstituent. For example, R₆ is, e.g., methyl, methoxy,methoxymethylene, fluoro, chloro, bromo or hydroxy.

In another embodiment, in the compound of Formula I, R₂ and R₃ arenon-hydrogen substituents. For example, R₂ and R₃ are, e.g.,independently, methyl, methoxy, methoxymethylene, fluoro, chloro, bromoor hydroxy. In another embodiment, in the compound of Formula I, R₂ andR₆ are non-hydrogen substituents. For example, R₂ and R₆ are, e.g.,independently, methyl, methoxy, methoxymethylene, fluoro, chloro, bromoor hydroxy. In another embodiment, in the compound of Formula I, R₂ andR₅ are non-hydrogen substituents. For example, R₂ and R₅ are, e.g.,independently, methyl, methoxy, methoxymethylene, fluoro, chloro, bromoor hydroxy. In another embodiment, in the compound of Formula I, R₃ andR₆ are non-hydrogen substituents. For example, R₃ and R₆ are, e.g.,independently, methyl, methoxy, methoxymethylene, fluoro, chloro, bromoor hydroxy. In another embodiment, in the compound of Formula I, R₃ andR₅ are non-hydrogen substituents. For example, R₃ and R₅ are, e.g.,independently, methyl, methoxy, methoxymethylene, fluoro, chloro, bromoor hydroxy. In another embodiment, in the compound of Formula I, R₆ andR₅ are non-hydrogen substituents. For example, R₅ and R₆ are, e.g.,independently, methyl, methoxy, methoxymethylene, fluoro, chloro, bromoor hydroxy.

In another embodiment, in the compound of Formula I, R₆ is methoxy, andR₁-R₅ are hydrogen. In another embodiment, in the compound of Formula I,R₂ is methyl or methoxy, and R₁, and R₃-R₆ are hydrogen. In anotherembodiment, in the compound of Formula I, R₃ is methyl and R₁-R₂, andR₄-R₅ are hydrogen. In another embodiment, in the compound of Formula I,R₅ is methoxy and R₁-R₄, and R₆ are hydrogen.

In one embodiment, at least one of R₂, R₆, and R₅ is not hydrogen. Inanother embodiment, at least one of R₂, R₆, and R₅ is fluoro, methyl,ethyl, isopropyl, or methoxy.

In one embodiment R₉ and R₁₀ together with the carbon to which they areattached are absent. In another embodiment, in the compound of FormulaI, R₁₁ and R₁₂ are each methyl. In another embodiment, R₁₁ and R₁₂ areeach ethyl. In another embodiment, R₁₁ and R₁₂, together with the carbonto which they are attached, are connected to form a spiro ring of size3, 4, 5, 6, or 7. The spiro ring is, e.g., a cyclopropyl ring.

In one embodiment, q is zero. In another embodiment, q is zero, and R₉and R₁₀ together with the carbon to which they are attached are absent.In another embodiment, q is zero, R₉ and R₁₀ together with the carbon towhich they are attached are absent, X and Y are absent. In anotherembodiment, q is zero, R₉ and R₁₀ together with the carbon to which theyare attached are absent, X and Y are absent, and the sum of m, n, o, andp is 2 or 3. In another embodiment, the compound of Formula I isselected from Compounds 1-106. In another embodiment, the compound ofFormula I is Compound 46.

In another aspect, the invention relates to a compound of Formula II:

or a pharmaceutically effective salt thereof, wherein: m, n, and o are,independently, 0, 1, 2, 3, 4, 5, or 6, X is absent, O, S, C(O), SO orSO₂; R₂, R₃, R₅, and R₆ are, independently H, F, Cl, Br, OH, CF₃, CH₃,CH₂CH₃, CH(CH₃)₂, cyclopropyl, OCH₃, OCF₃, CH₂OCH₃ or CH₂OCH₂CH₃; R₉,and R₁₀, are, independently, H, C₁, C₂, C₃, C₄, C₅ straight chain alkyl;C₂, C₃, C₄, C₅, C₆ branched alkyl, or R₉ and R₁₀ together with thecarbon to which they are attached, are connected to form a spiro ring ofsize 3, 4, 5, 6, or 7; Z is COOH, COOR₁₃, where R₁₃ is C₁, C₂, C₃, C₄,C₅, C₆ alkyl, CONHS(O)₂-alkyl, CONHS(O)₂-heteroalkyl, CONHS(O)₂-aryl,CONHS(O)₂-heteroaryl, S(O)₂NHCO-alkyl, S(O)₂NHCO-heteroalkyl,S(O)₂NHCO-aryl, S(O)₂NHCO-heteroaryl, CONHS(O)₂N-alkyl;CONHS(O)₂N-heteroalkyl; CONHS(O)₂N-aryl; CONHS(O)₂N-heteroaryl; ortetrazole, provided that when m is zero, X is absent.

In one embodiment, in the compound of Formula II, R₆ is not hydrogen orhalogen. In another embodiment, in the compound of Formula II, R₆ ismethyl, ethyl, isopropyl, methoxy, methoxymethylene or hydroxy. Inanother embodiment, in the compound of Formula II, R₂-R₃ and R₅ are eachhydrogen. In another embodiment, in the compound of Formula II, R₂-R₃and R₅-R₆ are independently hydrogen, methyl, ethyl, isopropyl, methoxy,methoxymethylene, fluoro, chloro, bromo or hydroxy.

In another embodiment, in the compound of Formula II, R₂ is anon-hydrogen substituent. For example, R₂ is, e.g., methyl, methoxy,methoxymethylene, fluoro, chloro, bromo or hydroxy. In anotherembodiment, in the compound of Formula II, R₃ is a non-hydrogensubstituent. For example, R₃ is, e.g., methyl, methoxy,methoxymethylene, fluoro, chloro, bromo or hydroxy. In anotherembodiment, in the compound of Formula II, R₅ is a non-hydrogensubstituent. For example, R₅ is, e.g., methyl, methoxy,methoxymethylene, fluoro, chloro, bromo or hydroxy. In anotherembodiment, R₆ is non-hydrogen e.g., R₆ is methyl, methoxy,methoxymethylene, fluoro, chloro, bromo or hydroxy. In anotherembodiment, in the compound of Formula II, R₂ and R₃ are non-hydrogensubstituents. For example, R₂ and R₃ are, e.g., independently, methyl,methoxy, methoxymethylene, fluoro, chloro, bromo or hydroxy. In anotherembodiment, in the compound of Formula II, R₂ and R₆ are non-hydrogensubstituents. For example, R₂ and R₆ are, e.g., independently, methyl,ethyl, isopropyl, methoxy, methoxymethylene, fluoro, chloro, bromo orhydroxy. In another embodiment, in the compound of Formula II, R₂ and R₅are non-hydrogen substituents. For example, R₂ and R₅ are, e.g.,independently, methyl, methoxy, methoxymethylene, fluoro, chloro, bromoor hydroxy. In another embodiment, in the compound of Formula II, R₃ andR₆ are non-hydrogen substituents. For example, R₃ and R₆ are, e.g.,independently, methyl, methoxy, methoxymethylene, fluoro, chloro, bromoor hydroxy. In another embodiment, in the compound of Formula II, R₃ andR₅ are non-hydrogen substituents. For example, R₃ and R₅ are, e.g.,independently, methyl, methoxy, methoxymethylene, fluoro, chloro, bromoor hydroxy. In another embodiment, in the compound of Formula II, R₆ andR₅ are non-hydrogen substituents. For example, R₆ and R₅ are, e.g.,independently, methyl, ethyl, isopropyl, methoxy, methoxymethylene,fluoro, chloro, bromo or hydroxy. In another embodiment, in the compoundof Formula II, R₆ is methoxy, and R₂, R₃ and R₅ are hydrogen. In anotherembodiment, in the compound of Formula II, R₂ is methyl or methoxy, andR₃, R₆ and R₅ are hydrogen. In another embodiment, in the compound ofFormula II, R₃ is methyl and R₂, R₆ and R₅ are hydrogen. In anotherembodiment, in the compound of Formula II, R₅ is methoxy and R₂, R₃ andR₆ are hydrogen.

In another embodiment, in the compound of Formula II, R₉ and R₁₀ areeach methyl. In another embodiment, R₉ and R₁₀ are each ethyl. Inanother embodiment, R₉ and R₁₀, together with the carbon to which theyare attached, are connected to form a spiro ring of size 3, 4, 5, 6, or7. The spiro ring is, e.g., a cyclopropyl ring.

In one embodiment, in the compound of Formula II, o is zero. In anotherembodiment, o is zero, and X is absent. In another embodiment, o iszero, X is absent, and the sum of m and n is 2 or 3.

In another aspect, the invention relates to a compound of Formula III:

or a pharmaceutically effective salt thereof, wherein: m and n are,independently, 0-4, X is absent, O, S, C(O), SO or SO₂; R₂, R₃, R₅, andR₆ are, independently, selected from H, F, Cl, Br, OH, CF₃, CH₃, CH₂CH₃,CH(CH₂)₂, OCH₃, CH₂OCH₃, and CH₂OCH₂CH₃; R₉, and R₁₀, are,independently, H, C₁, C₂, C₃, C₄, C₅ straight chain alkyl; C₂, C₃, C₄,C₅, C₆ branched alkyl, or R₉, and R₁₀, together with the carbon to whichthey are attached, are connected to form a spiro ring of size 3, 4, 5,6, or 7; Z is selected from CO₂H, CONHS(O)₂-alkyl, CONHS(O)₂-cycloalkyl,CONHS(O)₂-heteroalkyl, CONHS(O)₂-aryl, CONHS(O)₂-heteroaryl, andtetrazole; provided that when m is zero, X is absent.

In one embodiment, in the compound of Formula III, R₆ is not methyl. Inone embodiment, in the compound of Formula III, R₆ is not hydrogen or F,Cl, or Br. In one embodiment, in the compound of Formula III, R₆ is nothydrogen or F, Cl, or Br and R₂, R₃, and R₇ are hydrogen. In oneembodiment, R₂, R₃, and R₅ are hydrogen. In one embodiment, in thecompound of Formula III, R₂, R₃, R₅, and R₆ are, independently,hydrogen, halogen, methyl, ethyl, isopropyl, methoxymethylene, methoxyor hydroxy.

In one embodiment, in the compound of Formula III, R₆ is methoxy. Inanother embodiment, in the compound of Formula III, R₆ is methoxy, andR₂, R₃ and R₅ are hydrogen. In another embodiment, in the compound ofFormula III, R₂ is methyl or methoxy, and R₃, R₆ and R₅ are hydrogen. Inanother embodiment, in the compound of Formula III, R₃ is methyl and R₂,R₆ and R₅ are hydrogen. In another embodiment, in the compound ofFormula III, R₅ is methoxy and R₂, R₃ and R₆ are hydrogen.

In another embodiment, in the compound of Formula III, R₉ and R₁₀ areeach methyl. In another embodiment, R₉ and R₁₀, together with the carbonto which they are attached, are connected to form a spiro ring of size3, e.g., a cyclopropyl ring. In one embodiment, in the compound ofFormula III, X is absent. In another embodiment, X is absent, and thesum of m and n is 2 or 3.

In another aspect, the invention relates to a compound of Formula IV:

or a pharmaceutically effective salt thereof, wherein: t is 1, 2, 3, or4; R₂, R₃, R₅ and R₆ are, independently, H, F, Cl, Br, CF₃, CH₃, CH₂CH₃,CH(CH₃)₂, OH, OCH₃, CH₂OCH₃, or CH₂OCH₂CH₃; R₉-R₁₀ are H, CH₃, CH₂CH₃,or R₉ and R₁₀, together with the carbon to which they are attached, areconnected to form a spiro ring of size 3, 4, 5, 6, or 7; and Z isselected from CO₂H, CONHS(O)₂-alkyl, CONHS(O)₂-cycloalkyl,CONHS(O)₂-heteroalkyl, and tetrazole. In one embodiment, in the compoundof Formula IV, t is 1 or 2. In one embodiment, the compound of FormulaIV is selected from a compound of formula IVa, IVb, IVc, IVd, or IVe.

In another aspect the invention relates to a compound selected fromCompound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 32, 31, 33, 34, 35, 36,37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54,55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72,73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90,91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, or106. In another aspect the invention relates to Compound 46.

The above description sets forth rather broadly the more importantfeatures of the present invention in order that the detailed descriptionthereof that follows may be understood, and in order that the presentcontributions to the art may be better appreciated. Other objects andfeatures of the present invention will become apparent from thefollowing detailed description considered in conjunction with theexamples.

DETAILED DESCRIPTION

The details of one or more embodiments of the invention are set forth inthe accompanying description below. Although any methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the present invention, the exemplary methods andmaterials are now described. Other features, objects, and advantages ofthe invention will be apparent from the description. In thespecification, the singular forms also include the plural unless thecontext clearly dictates otherwise. Unless defined otherwise, alltechnical and scientific terms used herein have the same meaning ascommonly understood by one of ordinary skill in the art to which thisinvention belongs. In the case of conflict, the present specificationwill control.

DEFINITIONS

For convenience, certain terms used in the specification, examples andappended claims are collected here.

“Treating”, includes any effect, e.g., lessening, reducing, modulating,or eliminating, that results in the improvement of the condition,disease, disorder, etc.

“Alkyl” includes saturated aliphatic groups, including straight-chainalkyl groups (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl,octyl, nonyl, decyl), branched-chain alkyl groups (e.g., isopropyl,tert-butyl, isobutyl), cycloalkyl (e.g., alicyclic) groups (e.g.,cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), alkylsubstituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.“Alkyl” further includes alkyl groups that have oxygen, nitrogen, sulfuror phosphorous atoms replacing one or more hydrocarbon backbone carbonatoms. In certain embodiments, a straight chain or branched chain alkylhas six or fewer carbon atoms in its backbone (e.g., C₁-C₆ or C₁, C₂,C₃, C₄, C₅, C₆ for straight chain, C₃-C₆ or C₃, C₄, C₅, C₆ for branchedchain), and typically four or fewer. Likewise, typical cycloalkyls havefrom three to eight carbon atoms in their ring structure, for example,they have five or six carbons in the ring structure. “C₁-C₆” includesalkyl groups containing one to six carbon atoms.

The term “alkyl” also includes both “unsubstituted alkyls” and“substituted alkyls”, the latter of which refers to alkyl moietieshaving substituents replacing a hydrogen on one or more carbons of thehydrocarbon backbone. Such substituents can include, for example, alkyl,alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate,phosphonato, phosphinato, cyano, amino (including alkylamino,dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromaticor heteroaromatic moiety. Cycloalkyls can be further substituted, e.g.,with the substituents described above. An “alkylaryl” or an “aralkyl”moiety is an alkyl substituted with an aryl (e.g.,phenylmethyl(benzyl)). “Alkyl” also includes the side chains of naturaland unnatural amino acids.

“Aryl” includes groups with aromaticity, including 5- and 6-membered“unconjugated”, or single-ring, aromatic groups that may include fromzero to four heteroatoms, as well as “conjugated”, or multicyclic,systems with at least one aromatic ring. Examples of aryl groups includebenzene, phenyl, pyrrole, furan, thiophene, thiazole, isothiazole,imidazole, triazole, tetrazole, pyrazole, oxazole, isooxazole, pyridine,pyrazine, pyridazine, and pyrimidine, and the like. Furthermore, theterm “aryl” includes multicyclic aryl groups, e.g., tricyclic, bicyclic,e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole,benzoimidazole, benzothiophene, methylenedioxyphenyl, quinoline,isoquinoline, napthridine, indole, benzofuran, purine, benzofuran,deazapurine, or indolizine. Those aryl groups having heteroatoms in thering structure may also be referred to as “aryl heterocycles”,“heterocycles,” “heteroaryls” or “heteroaromatics”. The aromatic ringcan be substituted at one or more ring positions with such substituentsas described above, as for example, halogen, hydroxyl, alkoxy,alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl,aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl,aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl,alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino(including alkylamino, dialkylamino, arylamino, diarylamino, andalkylaryl amino), acyl amino (including alkylcarbonylamino,arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl,alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl,sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Arylgroups can also be fused or bridged with alicyclic or heterocyclicrings, which are not aromatic so as to form a multicyclic system (e.g.,tetralin, methylenedioxyphenyl).

“Alkenyl” includes unsaturated aliphatic groups analogous in length andpossible substitution to the alkyls described above, but that contain atleast one double bond. For example, the term “alkenyl” includesstraight-chain alkenyl groups (e.g., ethenyl, propenyl, butenyl,pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), branched-chainalkenyl groups, cycloalkenyl (e.g., alicyclic) groups (e.g.,cyclopropenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl,cyclooctenyl), alkyl or alkenyl substituted cycloalkenyl groups, andcycloalkyl or cycloalkenyl substituted alkenyl groups. The term“alkenyl” further includes alkenyl groups, which include oxygen,nitrogen, sulfur or phosphorous atoms replacing one or more hydrocarbonbackbone carbons. In certain embodiments, a straight chain or branchedchain alkenyl group has six or fewer carbon atoms in its backbone (e.g.,C₂-C₆ or C₂, C₃, C₄, C₅, C₆ for straight chain, C₃-C₆ or C₃, C₄, C₅, C₆for branched chain.) Likewise, cycloalkenyl groups may have from threeto eight carbon atoms in their ring structure, and typically have fiveor six carbons in the ring structure. The term “C₂-C₆” includes alkenylgroups containing two to six carbon atoms.

The term “alkenyl” also includes both “unsubstituted alkenyls” and“substituted alkenyls”, the latter of which refers to alkenyl moietieshaving substituents replacing a hydrogen on one or more hydrocarbonbackbone carbon atoms. Such substituents can include, for example, alkylgroups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl,phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino,dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromaticor heteroaromatic moiety.

“Alkynyl” includes unsaturated aliphatic groups analogous in length andpossible substitution to the alkyls described above, but which containat least one triple bond. For example, “alkynyl” includes straight-chainalkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl,heptynyl, octynyl, nonynyl, decynyl), branched-chain alkynyl groups, andcycloalkyl or cycloalkenyl substituted alkynyl groups. The term“alkynyl” further includes alkynyl groups having oxygen, nitrogen,sulfur or phosphorous atoms replacing one or more hydrocarbon backbonecarbons. In certain embodiments, a straight chain or branched chainalkynyl group has six or fewer carbon atoms in its backbone (e.g., C₂-C₆or C₂, C₃, C₄, C₅, C₆ for straight chain, C₃-C₆ or C₃, C₄, C₅, C₆ forbranched chain). The term “C₂-C₆” includes alkynyl groups containing twoto six carbon atoms.

The term “alkynyl” also includes both “unsubstituted alkynyls” and“substituted alkynyls”, the latter of which refers to alkynyl moietieshaving substituents replacing a hydrogen on one or more hydrocarbonbackbone carbon atoms. Such substituents can include, for example, alkylgroups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl,phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino,dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromaticor heteroaromatic moiety.

Unless the number of carbons is otherwise specified, “lower alkyl”includes an alkyl group, as defined above, but having from one to ten,typically from one to six, carbon atoms in its backbone structure.“Lower alkenyl” and “lower alkynyl” have chain lengths of, for example,2, 3, 4, or 5 carbon atoms.

“Acyl” includes compounds and moieties that contain the acyl radical(CH₃CO—) or a carbonyl group. “Substituted acyl” includes acyl groupswhere one or more of the hydrogen atoms are replaced by for example,alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl,phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino,dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromaticor heteroaromatic moiety.

“Acylamino” includes moieties wherein an acyl moiety is bonded to anamino group. For example, the term includes alkylcarbonylamino,arylcarbonylamino, carbamoyl and ureido groups.

“Aroyl” includes compounds and moieties with an aryl or heteroaromaticmoiety bound to a carbonyl group. Examples of aroyl groups includephenylcarboxy, naphthyl carboxy, etc. “Alkoxyalkyl”, “alkylaminoalkyl”and “thioalkoxyalkyl” include alkyl groups, as described above, whichfurther include oxygen, nitrogen or sulfur atoms replacing one or morehydrocarbon backbone carbon atoms, e.g., oxygen, nitrogen or sulfuratoms.

The term “alkoxy” or “alkoxyl” includes substituted and unsubstitutedalkyl, alkenyl, and alkynyl groups covalently linked to an oxygen atom.Examples of alkoxy groups (or alkoxyl radicals) include methoxy, ethoxy,isopropyloxy, propoxy, butoxy, and pentoxy groups. Examples ofsubstituted alkoxy groups include halogenated alkoxy groups. The alkoxygroups can be substituted with groups such as alkenyl, alkynyl, halogen,hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl,alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano,amino (including alkylamino, dialkylamino, arylamino, diarylamino, andalkylarylamino), acylamino (including alkylcarbonylamino,arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl,alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl,sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties.Examples of halogen substituted alkoxy groups include, but are notlimited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy,chloromethoxy, dichloromethoxy, and trichloromethoxy.

The terms “heterocyclyl” or “heterocyclic group” include closed ringstructures, e.g., 3, 4, 5, 6, 7, 8, 9, or 10, or 4, 5, 6, or 7-memberedrings, which include one or more heteroatoms. “Heteroatom” includesatoms of any element other than carbon or hydrogen. Examples ofheteroatoms include nitrogen, oxygen, sulfur and phosphorus.

Heterocyclyl groups can be saturated or unsaturated and includepyrrolidine, oxolane, thiolane, piperidine, piperazine, morpholine,lactones, lactams such as azetidinones and pyrrolidinones, sultams, andsultones. Heterocyclic groups such as pyrrole and furan can havearomatic character. They include fused ring structures such as quinolineand isoquinoline. Other examples of heterocyclic groups include pyridineand purine. The heterocyclic ring can be substituted at one or morepositions with such substituents as described above, as for example,halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl,aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato,phosphinato, cyano, amino (including alkyl amino, dialkylamino,arylamino, diarylamino, and alkylarylamino), acylamino (includingalkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino,imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates,sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,heterocyclyl, or an aromatic or heteroaromatic moiety. Heterocyclicgroups can also be substituted at one or more constituent atoms with,for example, a lower alkyl, a lower alkenyl, a lower alkoxy, a loweralkylthio, a lower alkylamino, a lower alkylcarboxyl, a nitro, ahydroxyl, —CF₃, or —CN, or the like.

The term “thiocarbonyl” or “thiocarboxy” includes compounds and moietieswhich contain a carbon connected with a double bond to a sulfur atom.

The term “ether” includes compounds or moieties which contain an oxygenbonded to two different carbon atoms or heteroatoms. For example, theterm includes “alkoxyalkyl” which refers to an alkyl, alkenyl, oralkynyl group covalently bonded to an oxygen atom which is covalentlybonded to another alkyl group.

The term “ester” includes compounds and moieties which contain a carbonor a heteroatom bound to an oxygen atom which is bonded to the carbon ofa carbonyl group. The term “ester” includes alkoxycarboxy groups such asmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl,pentoxycarbonyl, etc. The alkyl, alkenyl, or alkynyl groups are asdefined above.

The term “thioether” includes compounds and moieties which contain asulfur atom bonded to two different carbon or heteroatoms. Examples ofthioethers include, but are not limited to alkthioalkyls,alkthioalkenyls, and alkthioalkynyls. The term “alkthioalkyls” includecompounds with an alkyl, alkenyl, or alkynyl group bonded to a sulfuratom which is bonded to an alkyl group. Similarly, the term“alkthioalkenyls” and alkthioalkynyls” refer to compounds or moietieswherein an alkyl, alkenyl, or alkynyl group is bonded to a sulfur atomwhich is covalently bonded to an alkynyl group.

The term “hydroxy” or “hydroxyl” includes groups with an —OH or —O⁻.

The term “halogen” includes fluorine, bromine, chlorine, iodine, etc.The term “perhalogenated” generally refers to a moiety wherein allhydrogens are replaced by halogen atoms.

The term “non-hydrogen substituent” refers to substituents other thanhydrogen. Non-limiting examples include alkyl groups, alkoxy groups,halogen groups, hydroxyl groups, aryl groups, etc.

“Polycyclyl” or “polycyclic radical” refers to two or more cyclic rings(e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/orheterocyclyls) in which two or more carbons are common to two adjoiningrings. Rings that are joined through non-adjacent atoms are termed“bridged” rings. Each of the rings of the polycycle can be substitutedwith such substituents as described above, as for example, halogen,hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl,alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl,alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl,aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato,phosphinato, cyano, amino (including alkylamino, dialkylamino,arylamino, diarylamino, and alkylarylamino), acylamino (includingalkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino,imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates,alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkyl, alkylaryl, or anaromatic or heteroaromatic moiety.

An “anionic group,” as used herein, refers to a group that is negativelycharged at physiological pH. Typical anionic groups include carboxylate,sulfate, sulfonate, sulfinate, sulfamate, tetrazolyl, phosphate,phosphonate, phosphinate, or phosphorothioate or functional equivalentsthereof. “Functional equivalents” of anionic groups are intended toinclude bioisosteres, e.g., bioisosteres of a carboxylate group.Bioisosteres encompass both classical bioisosteric equivalents andnon-classical bioisosteric equivalents. Classical and non-classicalbioisosteres are known in the art (see, e.g., Silverman, R. B. TheOrganic Chemistry of Drug Design and Drug Action, Academic Press, Inc.:San Diego, Calif., 1992, pp. 19-23). One typical anionic group is acarboxylate.

The terms “crystal polymorphs” or “polymorphs” refer to the existence ofmore than one crystal form for a compound, salt or solvate thereof.Crystal polymorphs of the olanzapine-analog compounds are prepared bycrystallization under different conditions.

It will be noted that the structure of some of the compounds of theinvention include asymmetric carbon atoms. It is to be understoodaccordingly that the isomers arising from such asymmetry (e.g., allenantiomers and diastereomers) are included within the scope of theinvention, unless indicated otherwise. Such isomers can be obtained insubstantially pure form by classical separation techniques and bystereochemically controlled synthesis. Furthermore, the structures andother compounds and moieties discussed in this application also includeall tautomers thereof. Alkenes can include either the E- or Z-geometry,where appropriate.

The language “olanzapine-like compounds” or “olanzapine-analogcompounds” “olanzapine-like compounds” or “olanzapine derivativecompounds” is intended to include analogs of olanzapine that include atricyclic ring system, e.g. two aromatic rings flanking a seven memberednitrogen-containing ring bonded to a nitrogen of a piperidine ring(i.e., similar to that of olanzapine).

As used herein, the term “analog” refers to a chemical compound that isstructurally similar to another but differs slightly in composition (asin the replacement of one atom by an atom of a different element or inthe presence of a particular functional group, or the replacement of onefunctional group by another functional group). Thus, an analog is acompound that is similar or comparable in function and appearance, butnot in structure or origin to the reference compound. For example, thereference compound can be a reference compound such as olanzapine, andan analog is a substance possessing a chemical structure or chemicalproperties similar to those of the reference compound.

As defined herein, the term “derivative”, e.g., in the term “olanzapinederivatives”, refers to compounds that have a common core structure, andare substituted with various groups as described herein. For example,all of the compounds represented by formulae I-IVe are olanzapinederivatives, and have one of formulae I-IVe as a common core.

The term “bioisostere” refers to a compound resulting from the exchangeof an atom or of a group of atoms with another, broadly similar, atom orgroup of atoms. The objective of a bioisosteric replacement is to createa new compound with similar biological properties to the parentcompound. The bioisosteric replacement may be physicochemically ortopologically based. Examples of carboxylic acid bioisosteres includeacyl sulfonimides, tetrazoles, sulfonates, and phosphonates. See, e.g.,Patani and LaVoie, Chem. Rev. 96, 3147-3176 (1996). Thus, typical Zgroups are carboxylic acids, and carboxylic acid bioisosteres.

As used herein, the term “sleep disorder” includes conditions recognizedby one skilled in the art as sleep disorders, for example, conditionsknown in the art or conditions that are proposed to be sleep disordersor discovered to be sleep disorders. A sleep disorder also arises in asubject that has other medical disorders, diseases, or injuries, or in asubject being treated with other medications or medical treatments,where the subject, as a result, has difficulty falling asleep and/orremaining asleep, or experiences unrefreshing sleep or non-restorativesleep, e.g., the subject experiences sleep deprivation.

The term “treating a sleep disorder” also includes treating a sleepdisorder component of other disorders, such as CNS disorders (e.g.,mental or neurological disorders such as anxiety). Additionally, theterm “treating a sleep disorder” includes the beneficial effect ofameliorating other symptoms associated with the disorder.

The term “nonREM peak sleep time” is defined as an absolute peak amountof nonREM sleep per hour post treatment, with drug administrationoccurring at Circadian Time (CT) 18, which is 6 hours after lights offin a nocturnal laboratory rat when housed in a LD 12:12 (12-hours lightand 12 hours dark) light-dark cycle. The nominal criteria of 55% nonREMsleep per hour is equivalent to 33 minutes of nonREM sleep per hour.

As used herein, the term “cumulative nonREM sleep” is defined as the nettotal aggregate increase in the number of minutes of nonREM sleep,measured through out the entire duration of a drug's soporific effect,which typically, but not always occurs in the first 6 hourspost-treatment, adjusted for the net total aggregate number of minutesof nonREM sleep that occurred during the corresponding non-treatmentbaseline times of day recorded 24 hours earlier, relative to likevehicle control treatment.

As defined herein, the term “sleep bout” refers to a discrete episode ofcontinuous or near continuous sleep, comprised of nonREM sleep, REMsleep, or both nonREM and REM sleep stages, delimited prior and afterthe episode by greater than two contiguous 10 second epochs ofwakefulness.

As used herein, the term “longest sleep bout length” is defined as thetotal number of minutes an animal remains asleep (nonREM and/or REMsleep stages) during the single longest sleep episode or “bout” thatoccurred beginning in a given hour post-treatment. The “sleep boutlength” measurement criteria assumes sleep is measured continuously in10 second epochs, and is scored based upon the predominant state,computed or otherwise determined as a discrete sleep stage (where sleepstages are defined as nonREM sleep, REM sleep, or wakefulness) duringthe 10 second interval that defines the epoch.

The term “average sleep bout length” is defined as the average duration(in minutes) of every sleep bout that began in a given hour, independentof the individual duration of each episode or bout.

“Rebound insomnia” is defined as period of rebound, paradoxical, orcompensatory wakefulness that occurs after the sleep promoting effectsof a hypnotic or soporific agent.

“REM sleep inhibition” is defined as the reduction of REM sleep timepost-treatment at CT-18 (6 hours after lights-off; LD 12:12) or at CT-5(5 hours after lights-on; LD 12:12). Compounds that reduce REM sleeptime by greater than 15 minutes (relative to baseline and adjusted forvehicle treatment) when administered at either CT-18 or CT-5 areconsidered unacceptable.

Compared with NREM sleep or wakefulness, REM sleep causes ventilatorydepression and episodic cardiovascular changes. During rebound insomnia,the physiological effects of REM sleep are magnified and interrupt thenormal sleep cycles.

As defined herein, “disproportionate locomotor activity inhibition” is areduction of locomotor activity that exceeds the normal and expectedreduction in behavioral activity attributable to sleep.

“Combination therapy” (or “co-therapy”) includes the administration of acompound of the invention and at least a second agent as part of aspecific treatment regimen intended to provide the beneficial effectfrom the co-action of these therapeutic agents. The beneficial effect ofthe combination includes, but is not limited to, pharmacokinetic orpharmacodynamic co-action resulting from the combination of therapeuticagents. Administration of these therapeutic agents in combinationtypically is carried out over a defined time period (usually minutes,hours, days or weeks depending upon the combination selected).“Combination therapy” may, but generally is not, intended to encompassthe administration of two or more of these therapeutic agents as part ofseparate monotherapy regimens that incidentally and arbitrarily resultin the combinations of the present invention. “Combination therapy” isintended to embrace administration of these therapeutic agents in asequential manner, that is, wherein each therapeutic agent isadministered at a different time, as well as administration of thesetherapeutic agents, or at least two of the therapeutic agents, in asubstantially simultaneous manner. Substantially simultaneousadministration can be accomplished, for example, by administering to thesubject a single capsule having a fixed ratio of each therapeutic agentor in multiple, single capsules for each of the therapeutic agents.Sequential or substantially simultaneous administration of eachtherapeutic agent can be effected by any appropriate route including,but not limited to, oral routes, intravenous routes, intramuscularroutes, and direct absorption through mucous membrane tissues. Thetherapeutic agents can be administered by the same route or by differentroutes. For example, a first therapeutic agent of the combinationselected may be administered by intravenous injection while the othertherapeutic agents of the combination may be administered orally.Alternatively, for example, all therapeutic agents may be administeredorally or all therapeutic agents may be administered by intravenousinjection. The sequence in which the therapeutic agents are administeredis not narrowly critical. “Combination therapy” also embraces theadministration of the therapeutic agents as described above in furthercombination with other biologically active ingredients and non-drugtherapies (e.g., surgery or radiation treatment). Where the combinationtherapy further comprises a non-drug treatment, the non-drug treatmentmay be conducted at any suitable time so long as a beneficial effectfrom the co-action of the combination of the therapeutic agents andnon-drug treatment is achieved. For example, in appropriate cases, thebeneficial effect is still achieved when the non-drug treatment istemporally removed from the administration of the therapeutic agents,perhaps by days or even weeks.

The terms “parenteral administration” and “administered parenterally” asused herein refer to modes of administration other than enteral andtopical administration, usually by injection, and includes, withoutlimitation, intravenous, intramuscular, intra-arterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular,subarachnoid, intraspinal and intrasternal injection and infusion.

The term “pulmonary” as used herein refers to any part, tissue or organwhose primary function is gas exchange with the external environment,e.g., O₂/CO₂ exchange, within a patient. “Pulmonary” typically refers tothe tissues of the respiratory tract. Thus, the phrase “pulmonaryadministration” refers to administering the formulations describedherein to any part, tissue or organ whose primary function is gasexchange with the external environment (e.g., mouth, nose, pharynx,oropharynx, laryngopharynx, larynx, trachea, carina, bronchi,bronchioles, alveoli). For purposes of the present invention,“pulmonary” also includes a tissue or cavity that is contingent to therespiratory tract, in particular, the sinuses.

An “effective amount” of a compound of the disclosed invention is thequantity which, when administered to a subject in need of treatment,ameliorates symptoms arising from a sleep disorder, e.g., results in thesubject falling asleep more rapidly, results in more refreshing sleep,reduces duration or frequency of waking during a sleep period, orreduces the duration, frequency, or intensity of other dyssomnias,parasomnias. The amount of the disclosed compound to be administered toa subject will depend on the particular disorder, the mode ofadministration, co-administered compounds, if any, and thecharacteristics of the subject, such as general health, other diseases,age, sex, genotype, body weight and tolerance to drugs. The skilledartisan will be able to determine appropriate dosages depending on theseand other factors.

A “pharmaceutically acceptable salt” or “salt” of the disclosed compoundis a product of the disclosed compound that contains an ionic bond, andis typically produced by reacting the disclosed compound with either anacid or a base, suitable for administering to a subject.

A “pharmaceutical composition” is a formulation containing the disclosedcompounds in a form suitable for administration to a subject. In oneembodiment, the pharmaceutical composition is in bulk or in unit dosageform. The unit dosage form is any of a variety of forms, including, forexample, a capsule, an IV bag, a tablet, a single pump on an aerosolinhaler, or a vial. The quantity of active ingredient (e.g., aformulation of the disclosed compound or salts thereof) in a unit doseof composition is an effective amount and is varied according to theparticular treatment involved. One skilled in the art will appreciatethat it is sometimes necessary to make routine variations to the dosagedepending on the age and condition of the patient. The dosage will alsodepend on the route of administration. A variety of routes arecontemplated, including oral, pulmonary, rectal, parenteral,transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal,intranasal, and the like. Dosage forms for the topical or transdermaladministration of a compound of this invention include powders, sprays,ointments, pastes, creams, lotions, gels, solutions, patches andinhalants. In one embodiment, the active compound is mixed under sterileconditions with a pharmaceutically acceptable carrier, and with anypreservatives, buffers, or propellants that are required.

The term “flash dose” refers to compound formulations that are rapidlydispersing dosage forms.

The term “immediate release” is defined as a release of compound from adosage form in a relatively brief period of time, generally up to about60 minutes. The term “modified release” is defined to include delayedrelease, extended release, and pulsed release. The term “pulsed release”is defined as a series of releases of drug from a dosage form. The term“sustained release” or “extended release” is defined as continuousrelease of a compound from a dosage form over a prolonged period.

A “subject” includes mammals, e.g., humans, companion animals (e.g.,dogs, cats, birds, and the like), farm animals (e.g., cows, sheep, pigs,horses, fowl, and the like) and laboratory animals (e.g., rats, mice,guinea pigs, birds, and the like). Typically, the subject is human.

The invention provides a method of modulating sleep by administering aneffective amount of a olanzapine analog of the invention, which is amoiety that antagonizes a histamine receptor or a collection ofhistamine receptors. The invention also relates to novel olanzapineanalogs.

Effective sleep modulators have certain characteristics that correspondwith increased efficacy and decreased side effects. Thesecharacteristics include a desired half-life in a subject, controlledonset of desired sedative effects, and minimal to no detectable effecton psychomotor or other central nervous system (CNS) side effects (e.g.,memory deficits, decreased muscle tone, drooping eyelids or drowsiness).For example, effective sleep modulators have a half life in humans ofless than 7 hours, less than 6 hours, less than 5 hours, less than 4hours, approximately 3 hours, or in the range of 3 to 7 hours.

One approach to developing an effective sleep modulator is strategicallyderivitizing a known compound or family of compounds with sleepmodulating activity. Derivitizing may enhance one or more biologicalproperties to allow a compound to perform in an improved manner.Examples of favorable biological properties include, but are notlimited, to induction of a discrete sleep or hypnotic state, activity ofthe therapeutic compound for a discrete period of time, penetrationthrough the blood brain barrier into the CNS, e.g., resulting fromlipophilicity of substituents or conformational lipophilicity (i.e.,lipophilicity as a result of a particular conformation, such as internalsalt formation between a carboxylate anion and a protonated amine),modulation of the half-life of the therapeutic compound, an alterationof charge, an alteration of pharmacokinetics, an alteration of log P bya value of one or more, increased receptor selectivity, reducedperipheral half-life, the ability to increase dosage, increasedperipheral elimination, decreased anti-muscarinic activity, decreasedanti-cholinergic, and any combination thereof.

Derivitizing results in a variety of effects and alter differentmechanisms of action. For example, in some circumstances, a compoundcontaining a particular functional group, such as, e.g., an ester,carboxylic acid, or alcohol group, possesses an improved selectivity fora desired receptor versus undesired receptors when compared with acompound without this group. In other circumstances, the compoundcontaining the particular functional group is more active as atherapeutic agent for treating sleep disorders than the correspondingcompound without this group. The effect of the derivitized compounddepends on the identity of the addition.

By derivitizing a compound in order to enhance favorable biologicalproperties and decrease undesirable side effects, it is possible toimplement a strategy based on potential mechanistic effects orinteractions. For example, in some compounds, the presence of acarboxylic acid results in the ability to form an intramolecular ionicbond that includes the corresponding carboxylate ion, e.g., zwitterionspecies formation with a nitrogen atom within the compound or saltbridge formation. These interactions result in favorable biologicaleffects such as conformational lipophilicity, i.e., increasedlipophilicity as a result of a particular conformation, such as internalsalt formation between a carboxylate anion and a protonated amine. Suchconformational lipophilicity allows penetration through the blood brainbarrier into the CNS, despite that the presence of two polar ions isgenerally thought to inhibit crossing of the non-polar blood-brainbarrier. Another benefit of the presence of the carboxylic acid is animproved ability of the compound to bind selectively to the desiredreceptor.

Compounds of the invention can also be derivitized to produce prodrugs.“Prodrug” includes a precursor form of the drug which is metabolicallyconverted in vivo to produce the active drug. The invention furthercontemplates the use of prodrugs which are converted in vivo to thesleep modulating compounds used in the methods of the invention (see,e.g., R. B. Silverman, 1992, “The Organic Chemistry of Drug Design andDrug Action”, Academic Press, Chp. 8). Such prodrugs can be used toalter the biodistribution (e.g., to allow compounds which would nottypically cross the blood-brain barrier to cross the blood-brainbarrier) or the pharmacokinetics of the sleep modulating compound. Forexample, an anionic group, e.g., a carboxylate, sulfate or sulfonate,can be esterified, e.g., with an alkyl group (e.g., a methyl group) or aphenyl group, to yield an ester. When the ester is administered to asubject, the ester is cleaved, enzymatically or non-enzymatically,reductively or hydrolytically, to reveal the anionic group. Such anester can be cyclic, e.g., a cyclic sulfate or sulfone, or two or moreanionic moieties may be esterified through a linking group. An anionicgroup can be esterified with moieties (e.g., acyloxymethyl esters) whichare cleaved to reveal an intermediate sleep modulating compound whichsubsequently decomposes to yield the active sleep modulating compound.In one embodiment, the prodrug is a reduced form of a carboxylate,sulfate or sulfonate, e.g., an alcohol or thiol, which is oxidized invivo to the sleep modulating compound. Furthermore, an anionic moietycan be esterified to a group which is actively transported in vivo, orwhich is selectively taken up by target organs.

This strategy is applied to sleep modulating compounds to improve theireffectiveness and safety in clinical use. One group of compounds usefulin modulating sleep is related to olanzapine, which is apsychotherapeutic agent belonging to the family of compounds commonlyknown as atypical antipsychotics. Olanzapine is a thienobenzodiazepineantipsychotic agent, which produces pharmacological responses in variousanimal species which are characteristic of those seen with the majorityof antipsychotic drugs. Olanzapine is recommended for treatingschizophrenia.

In one aspect, the invention provides a method of modulating sleep in asubject by administering a therapeutically effective amount of acompound having the formula of Formula I:

or a pharmaceutically effective salt thereof, wherein: m, n, o, p, qare, independently, an integer from 0, 1, 2, 3, 4, 5, or 6; A and B are,independently, O, S, NR₇, or C(R₈)₂; X and Y are, independently, absent,O, S, C(O), SO or SO₂; R₁, R₂, R₃, R₄, R₅, R₆, R₇, and R₈ are,independently, H, F, Cl, Br, OH, CH₃, C₂, C₃, C₄, C₅, C₆ straight chainalkyl, C₃, C₄, C₅, C₆ branched alkyl, C₃, C₄, C₅, C₆, C₇ cycloalkyl, C₃,C₄, C₅, C₆, C₇ heterocyclyl, OCH₃, OCF₃, CH₂OCH₃, CH₂CH₂OCH₃,CH₂OCH₂CH₃, C₁, C₂, C₃, C₄, C₅, C₆ hydroxyalkyl, or C₁, C₂, C₃, C₅, C₆alkoxy; any hydrogen in the CH₂ groups in the linker is optionallysubstituted with H, F, Cl, OH, Br, CF₃, CH₃, C₂, C₃, C₄, C₅, C₆ straightchain alkyl, C₃, C₄, C₅, C₆ branched alkyl, C₃, C₄, C₅, C₆, C₇cycloalkyl, C₃, C₄, C₅, C₆, C₇ heterocyclyl, OCH₃, OCF₃, CH₂OCH₃,CH₂CH₂OCH₃, CH₂OCH₂CH₃, C₁-C₆ hydroxyalkyl; or C₁, C₂, C₃, C₄, C₅, C₆alkoxy; R₉, R₁₀, R₁₁, and R₁₂ are, independently, H, C₁, C₂, C₃, C₄, C₅straight chain alkyl, C₂, C₃, C₄, C₅, C₆ branched alkyl, or R₉ and R₁₀together with the carbon to which they are attached are absent or areconnected to form a spiro ring of size 3, 4, 5, 6, or 7, or R₁₁ and R₁₂together with the carbon to which they are attached are connected toform a spiro ring of size 3, 4, 5, 6, or 7, or substituents on twodifferent carbon atoms are connected to form a ring of size 3, 4, 5, 6,or 7; Z is selected from CO₂H, CO₂R₁₃, where R₁₃ is C₁-C₆ alkyl;CONR₁₄R₁₅, where R₁₄ and R₁₅ are, independently, hydrogen or loweralkyl; CONHS(O)₂-alkyl, CONHS(O)₂-cycloalkyl, CONHS(O)₂-heteroalkyl,CONHS(O)₂-aryl, CONHS(O)₂-heteroaryl, S(O)₂NHCO-alkyl,S(O)₂NHCO-cycloalkyl, S(O)₂NHCO-heteroalkyl, S(O)₂NHCO-aryl,S(O)₂NHCO-heteroaryl, CONHS(O)₂N-alkyl, CONHS(O)₂N-cycloalkyl,CONHS(O)₂N-heteroalkyl, CONHS(O)₂N-aryl, CONHS(O)₂N-heteroaryl, SO₃H,SO₂H, S(O)NHCO-alkyl, S(O)NHCO-aryl, S(O)NHCO-heteroaryl, P(O)(OH)₂,P(O)OH,

(tetrazole), or

provided that when m is zero, X is absent.

In one embodiment, the compounds of Formula I for use in the methods ofthe invention have one or more of the following characteristics: aninhibition constant (K_(i)) with regard to H1 receptor binding of lessthan 500 nM; a K_(i) with regard to off target binding to an off targetselected from M1, M2, M3, D1, D2, α1 and α2 that is greater than 1,000nm and/or more than 10 times greater than the K_(i) with regard to theH1 receptor; a nonREM peak time value that is greater than 55% nonREMsleep per hour by the third hour after the compound is administered to asubject; a cumulative total increase in nonREM sleep of not less than 20minutes for compound doses that produce maximum sleep consolidation; alongest sleep bout that is greater than 13 minutes in duration; netlongest sleep bout post treatment is greater than or equal to 3 minuteswhen adjusted using a baseline value obtained at least 24 hours prior toadministration of the compound to a subject; an average sleep bout thatis greater than 5 minutes at absolute peak; administration of thecompound to a subject does not produce appreciable amounts of reboundinsomnia; administration of the compound to a subject does notappreciably inhibit REM sleep; and administration of the compound to asubject does not disproportionately inhibit locomotor activity relativeto the normal effects of sleep.

In another embodiment, the compound of Formula I for use in the methodsof the invention has one or more of the following characteristics: aninhibition constant (K_(i)) with regard to H1 receptor binding of lessthan 300 nM; a K_(i) with regard to off target binding to an off targetselected from M1, M2, M3, D1, D2, α1 and α2 that is greater than 1 μm; anonREM peak time value that is greater than 55% nonREM sleep per hour bythe third hour after the compound is administered to a subject; acumulative total increase in nonREM sleep of not less than 20 minutesfor compound doses that produce maximum sleep consolidation; a longestsleep bout that is greater than 13 minutes in duration; net longestsleep bout post treatment is greater than or equal to 3 minutes whenadjusted using a baseline value obtained at least 24 hours prior toadministration of the compound to a subject; an average sleep bout thatis greater than 5 minutes at absolute peak; administration of thecompound to a subject does not produce appreciable amounts of reboundinsomnia; administration of the compound to a subject does notappreciably inhibit REM sleep; and administration of the compound to asubject does not disproportionately inhibit locomotor activity relativeto the normal effects of sleep.

In another embodiment, the compound of Formula I for use in the methodsof the invention has one or more of the following characteristics: aninhibition constant (K_(i)) with regard to H1 receptor binding of lessthan 150 nM; a K_(i) with regard to off target binding to an off targetselected from M1, M2, and M3, that is greater than 10 μM; a nonREM peaktime value that is greater than 55% nonREM sleep per hour by the thirdhour after the compound is administered to a subject; a cumulative totalincrease in nonREM sleep not less than 20 minutes for compound dosesthat produce maximum sleep consolidation; a longest sleep bout that isgreater than 17 minutes in duration; net longest sleep bout posttreatment is greater than or equal to 5 minutes when adjusted using abaseline value obtained at least 24 hours prior to administration of thecompound to a subject; an average sleep bout that is greater than 6minutes at absolute peak; administration of the compound to a subjectdoes not produce appreciable amounts of rebound insomnia; administrationof the compound to a subject does not appreciably inhibit REM sleep; andadministration of the compound to a subject does not disproportionatelyinhibit locomotor activity or motor tone relative to the normal effectsof sleep.

As used herein, the “linker” is the chain of atoms connecting thepiperazine nitrogen to the Z group.

The methods of the invention are used to treat a variety of subjects,including, for example, humans, companion animals, farm animals,laboratory animals and wild animals.

In one embodiment, the compound used in the method of modulating sleepis Compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35,36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53,54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71,72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89,90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105 or106.

In one embodiment, the compound used in the method of modulating sleepis Compound 46.

In one embodiment, R₉ and R₁₀ and the carbon they are attached to areabsent. In one embodiment, R₉ and R₁₀, together with the carbon to whichthey are attached, are connected to form a spiro ring of size 3, 4, 5,6, or 7. In one embodiment, R₁₁ and R₁₂, together with the carbon towhich they are attached, are connected to form a spiro ring of size 3,4, 5, 6, or 7. For example, R₉ and R₁₀ together with the carbon to whichthey are attached or R₁₁ and R₁₂ together with the carbon to which theyare attached, are connected to form a spiro 3-membered cyclopropyl ring.

In one embodiment, Z is CO₂H, tetrazole, or sulfonamide. In oneembodiment, Z is a sulfonamide. Typical sulfonamides include acylsulfonamides. For example, Z can have the formula

where W is a substituent chosen as needed to modulate the effects of thepolar surface area of the Z moiety such that the desired level of oralabsorption, CNS penetration, and rate of excretion into urine or bile isobtained. Examples of useful W substituents for this purpose include analkyl group (optionally containing a double or triple bond), acycloalkyl group (optionally containing a double bond), a heterocyclylgroup, an aryl group or a heteroaryl group, both optionally substituted,such as those shown below:

(where V is one or more side chains selected to modulate the pKa of theacylsulfonamide moiety, or to affect the physical or metabolicproperties of the compound. Examples of V side chains include halogenssuch as F, Cl, or Br; C₁-C₆ alkoxy groups such as OCH₃ or OCH₂CH₃; C₁,C₂, C₃, C₄, C₅, C₆ alkyl or C₃, C₄, C₅, C₆, C₇, C₈ cycloalkyl groupssuch as CH₃ or CF₃, cyclopropyl; heteroatom substituted C₁, C₂, C₃, C₄,C₅, C₆ alkyl or C₃, C₄, C₅, C₆, C₇, C₈ cycloalkyl, such as CH₂OCH₃, orCH₂OCH₂CH₃; electron withdrawing groups such as CN, a ketone, an amide,or a sulfone.

(and pyridyl isomers),

(and pyrimidine isomers), and

In one embodiment, Z is a sulfamide. Typical sulfamides include acylsulfamides. For example, Z can have the formula

where Ra and Rb are, independently, for example an alkyl group, acycloalkyl group, a heterocyclyl group, an aryl group or a heteroarylgroup, optionally substituted. Examples include the following:

(where V is a halogen such as F, Cl, or Br; C₁, C₂, C₃, C₄, C₅, C₆alkoxy such as OCH₃ or OCH₂CH₃; C₁, C₂, C₃, C₄, C₅, C₆ alkyl or C₃, C₄,C₅, C₆, C₇, C₈ cycloalkyl such as CH₃ or CF₃, cyclopropyl; heteroatomsubstituted C₁, C₂, C₃, C₄, C₅, C₆ alkyl or C₃, C₄, C₅, C₆, C₇, C₈cycloalkyl, such as CH₂OCH₃, or CH₂OCH₂CH₃; an electron withdrawinggroup such as CN, a ketone, an amide, or a sulfone),

(and pyridyl isomers),

(and pyrimidine isomers).

In another embodiment, when Z is COOH, at least one of R₁-R₆, and atleast one of R₉-R₁₂, are not hydrogen.

In one embodiment, R₆ is not hydrogen. In another embodiment, R₁-R₅ areeach hydrogen and R₆ is not hydrogen.

In one embodiment, at least one of R₁-R₆ is not hydrogen, and theremaining R₁-R₆ are hydrogen. In another embodiment, at least two ofR₁-R₆ are not hydrogen, and the remaining R₁-R₆ are hydrogen. In anotherembodiment, at least three of R₁-R₆ are not hydrogen and the remainingR₁-R₆ are hydrogen. In another embodiment, at least four of R₁-R₆ arenot hydrogen and the remaining R₁-R₆ are hydrogen. In one embodiment, R₂is not hydrogen. In one embodiment, R₃ is not hydrogen. In oneembodiment, R₆ is not hydrogen. In one embodiment, R₅ is not hydrogen.In one embodiment, R₃ and R₆ are not hydrogen. In another embodiment, R₂and R₆ are not hydrogen. In another embodiment, R₃ and R₅ are nothydrogen. In another embodiment, R₂ and R₅ are not hydrogen. In anotherembodiment, R₂ and R₃ are not hydrogen. In another embodiment, R₅ and R₆are not hydrogen.

In one embodiment, at least one of R₁-R₆ is methyl, ethyl, isopropyl,chloro, fluoro, bromo, hydroxy, methoxymethylene or methoxy. In anotherembodiment, R₂ is methyl, chloro, fluoro, bromo, hydroxy,methoxymethylene or methoxy. In another embodiment, R₃ is methyl,chloro, fluoro, bromo, hydroxy, methoxymethylene or methoxy. In anotherembodiment, R₆ is methyl, ethyl, isopropyl, chloro, fluoro, bromo,hydroxy, methoxymethylene or methoxy. In another embodiment, R₅ ismethyl, chloro, fluoro, bromo, hydroxy, methoxymethylene or methoxy.

In another embodiment, at least two of R₁-R₆ are methyl, ethyl,isopropyl, chloro, fluoro, bromo, hydroxy, methoxymethylene or methoxy.In another embodiment, at least two of R₁-R₆ are methyl, ethyl,isopropyl, methoxymethylene, chloro, fluoro, bromo, hydroxy, or methoxy;and Z is COOH. In another embodiment, at least two of R₁-R₆ are methyl,ethyl, isopropyl, methoxymethylene, chloro, fluoro, bromo, hydroxy, ormethoxy; R₉ and R₁₀ are hydrogen; and Z is COOH.

In one embodiment, R₃ and R₆ are both methyl, methoxy, hydroxy,methoxymethylene, chloro, fluoro, or bromo, and the remaining R₁-R₂, andR₄-R₅ are hydrogen. In another embodiment, R₂ and R₆ are both methyl,methoxy, hydroxy, methoxymethylene, chloro, fluoro, or bromo, and theremaining R₁, and R₃-R₅ are hydrogen. In one embodiment, R₃ and R₅ areboth methyl, methoxy, hydroxy, methoxymethylene, chloro, fluoro, orbromo, and the remaining R₁-R₂, R₄, and R₆ are hydrogen. In oneembodiment, R₂ and R₅ are both methyl, methoxy, hydroxy,methoxymethylene, chloro, fluoro, or bromo, and the remaining R₁, R₃-R₄,and R₆ are hydrogen. In one embodiment, R₂ and R₃ are both methyl,methoxy, hydroxy, methoxymethylene, chloro, fluoro, or bromo, and theremaining R₁ and R₄-R₆ are hydrogen.

In one embodiment, R₆ is methyl. In one embodiment, R₆ is methyl and R₂or R₃ is methyl, methoxy, methoxymethylene, chloro, fluoro, or bromo. Inanother embodiment, R₆ is fluoro and R₂ or R₃ is methyl,methoxymethylene, or methoxy. In one embodiment, R₆ is methoxy. In oneembodiment, R₆ is methoxy and R₂ or R₃ is methyl, methoxy, hydroxy,methoxymethylene, chloro, fluoro, or bromo. In another embodiment, R₆ isfluoro and R₂ or R₃ is methoxy.

In one embodiment, R₉ and R₁₀ are hydrogen.

In one embodiment, R₉ and R₁₀ are methyl. In another embodiment, R₉ andR₁₀ are methyl, R₆ is hydrogen or halogen, and R₁-R₅ are hydrogen. Inanother embodiment, R₉ and R₁₀ are methyl, R₆ is hydrogen, methyl, orhalogen, R₁-R₅ are hydrogen, and Z is COOH.

In one embodiment, R₉ and R₁₀ are ethyl. In another embodiment, R₉ andR₁₀ are ethyl, R₆ is hydrogen, methyl, or halogen, and R₁-R₅ arehydrogen. In another embodiment, R₉ and R₁₀ are ethyl, R₆ is hydrogen,methyl, or halogen, R₁-R₅ are hydrogen, and Z is COOH.

In one embodiment, R₉ and R₁₀ and the carbon to which they are attachedare connected to form a three-membered spiro (cyclopropyl) ring. Inanother embodiment, R₉ and R₁₀ and the carbon to which they are attachedare connected to form a three-membered spiro (cyclopropyl) ring, R₆ ishydrogen, methyl, or halogen, and R₁-R₅ are hydrogen. In anotherembodiment, R₉ and R₁₀ and the carbon to which they are attached areconnected to form a three-membered spiro (cyclopropyl) ring, R₆ ishydrogen, methyl, or halogen, and R₁-R₅ are hydrogen and Z is COOH.

In another embodiment, R₉ and R₁₀ are methyl, R₆ is methyl or methoxy,and R₁-R₅ are hydrogen. In another embodiment, R₉ and R₁₀ are methyl, R₆is methyl or methoxy, R₁-R₅ are hydrogen, and Z is COOH.

In another embodiment, R₉ and R₁₀ are ethyl, R₆ is methyl or methoxy,and R₁-R₅ are hydrogen. In another embodiment, R₉ and R₁₀ are ethyl, R₆is methyl or methoxy, R₁-R₅ are hydrogen, and Z is COOH.

In another embodiment, R₉ and R₁₀ and the carbon to which they areattached are connected to form a three-membered spiro (cyclopropyl)ring, R₆ is methyl or methoxy, and R₁-R₅ are hydrogen. In anotherembodiment, R₉ and R₁₀ and the carbon to which they are attached areconnected to form a three-membered spiro (cyclopropyl) ring, R₆ ismethyl or methoxy, and R₁-R₅ are hydrogen and Z is COOH.

In one embodiment, R₁₁ and R₁₂ are methyl. In another embodiment, R₁₁and R₁₂ are methyl, R₆ is hydrogen, methyl, or halogen, and R₁-R₅ arehydrogen. In another embodiment, R₁₁ and R₁₂ are methyl, R₆ is hydrogen,methyl, or halogen, R₁-R₅ are hydrogen, and Z is COOH.

In one embodiment, R₁₁ and R₁₂ are ethyl. In another embodiment, R₁₁ andR₁₂ are ethyl, R₆ is hydrogen, methyl, or halogen, and R₁-R₅ arehydrogen. In another embodiment, R₁₁ and R₁₂ are ethyl, R₆ is hydrogen,methyl, or halogen, R₁-R₅ are hydrogen, and Z is COOH.

In one embodiment, R₁₁ and R₁₂ and the carbon to which they are attachedare connected to form a three-membered spiro (cyclopropyl) ring. Inanother embodiment, R₁₁ and R₁₂ and the carbon to which they areattached are connected to form a three-membered spiro (cyclopropyl)ring, R₆ is hydrogen, methyl, or halogen, and R₁-R₅ are hydrogen. Inanother embodiment, R₁₁ and R₁₂ and the carbon to which they areattached are connected to form a three-membered spiro (cyclopropyl)ring, R₆ is hydrogen, methyl, or halogen, and R₁-R₅ are hydrogen and Zis COOH.

In one embodiment, R₁₁ and R₁₂ are methyl and R₆ is methyl or methoxy.In another embodiment, R₁₁ and R₁₂ are methyl, R₆ is methyl or methoxy,and R₁-R₅ are hydrogen. In another embodiment, R₁₁ and R₁₂ are methyl,R₆ is methyl or methoxy, R₁-R₅ are hydrogen, and Z is COOH.

In one embodiment, R₁₁ and R₁₂ are ethyl and R₆ is methyl or methoxy. Inanother embodiment, R₁₁, and R₁₂ are ethyl, R₆ is methyl or methoxy, andR₁-R₅ are hydrogen. In another embodiment, R₁₁ and R₁₂ are ethyl, R₆ ismethyl or methoxy, R₁-R₅ are hydrogen, and Z is COOH.

In one embodiment, R₁₁ and R₁₂ and the carbon to which they are attachedare connected to form a three-membered spiro (cyclopropyl) ring and R₆is methyl or methoxy. In another embodiment, R₁₁ and R₁₂ and the carbonto which they are attached are connected to form a three-membered spiro(cyclopropyl) ring, R₆ is methyl or methoxy, and R₁-R₅ are hydrogen. Inanother embodiment, R₁₁ and R₁₂ and the carbon to which they areattached are connected to form a three-membered spiro (cyclopropyl)ring, R₆ is methyl or methoxy, and R₁-R₅ are hydrogen and Z is COOH.

In one embodiment, in the compound of Formula I used in the method ofthe invention, q is zero. In another embodiment, q is zero, and R₉ andR₁₀ together with the carbon to which they are attached are absent. Inanother embodiment, q is zero, R₉ and R₁₀ together with the carbon towhich they are attached are absent, X and Y are absent. In anotherembodiment, q is zero, R₉ and R₁₀ together with the carbon to which theyare attached are absent, X and Y are absent, and the sum of m, n, o, andp is 2 or 3.

In one aspect, the compounds of the invention are used to modulatesleep, e.g., by decreasing the time to sleep onset, increasing theaverage sleep bout length, and/or increasing the maximum sleep boutlength. In another aspect, the olanzapine analogs of the invention areused to treat a sleep disorder. For example, the olanzapine analogs ofthe invention are used to treat circadian rhythm abnormality, insomnia,parasomnia, sleep apnea syndrome, narcolepsy and/or hypersomnia.

In one embodiment, the olanzapine analogs of the invention are used inthe treatment of a circadian rhythm abnormality, such as, for example,jet lag, shift-work disorders, delayed sleep phase syndrome, advancedsleep phase syndrome and non-24 hour sleep-wake disorder.

In another embodiment, the olanzapine analogs are used in the treatmentof insomnia, including, for example, extrinsic insomnia,psychophysiologic insomnia, altitude insomnia, restless leg syndrome,periodic limb movement disorder, medication-dependent insomnia,drug-dependent insomnia, alcohol-dependent insomnia and insomniaassociated with mental disorders.

In one embodiment, the olanzapine analogs of the invention are used totreat a parasomnia disorder, such as, e.g., somnambulism, pavornocturnus, REM sleep behavior disorder, sleep bruxism and sleepenuresis.

In another embodiment, the olanzapine analogs are used to treat a sleepapnea disorder, such as, for example, central sleep apnea, obstructivesleep apnea and mixed sleep apnea.

Pharmaceutical compositions that include a compound of Formula I or apharmaceutically acceptable salt thereof are used in the methods ofmodulating sleep. In one embodiment, the compound of Formula I or apharmaceutically acceptable salt thereof is co-administered with one ormore additional therapies.

In another aspect, the present invention provides a method of modulatingsleep in a subject by administering a therapeutically effective amountof a compound having the formula of Formula II:

or a pharmaceutically effective salt thereof, wherein m, n, and o are,independently, 0, 1, 2, 3, 4, 5, or 6; X is absent, O, S, C(O), SO orSO₂; R₂, R₃, R₅, and R₆ are, independently, selected from H, F, Cl, Br,CF₃, CH₃, CH₂CH₃, CH(CH₃)₂, cyclopropyl, OH, OCH₃, OCF₃, CH₂OCH₃ andCH₂OCH₂CH₃; R₉, and R₁₀, are, independently, H, C₁, C₂, C₃, C₄, C₅straight chain alkyl; C₂, C₃, C₄, C₅, C₆ branched alkyl, or R₉ and R₁₀together with the carbon to which they are attached, are connected toform a spiro ring of size 3, 4, 5, 6, or 7; and Z is COOH, COOR₁₃, whereR₁₃ is C₁, C₂, C₃, C₄, C₅, C₆ alkyl, CONHS(O)₂-alkyl,CONHS(O)₂-heteroalkyl, CONHS(O)₂-aryl, CONHS(O)₂-heteroaryl,S(O)₂NHCO-alkyl, S(O)₂NHCO-heteroalkyl, S(O)₂NHCO-aryl,S(O)₂NHCO-heteroaryl, CONHS(O)₂N-alkyl; CONHS(O)₂N-heteroalkyl;CONHS(O)₂N-aryl; CONHS(O)₂N-heteroaryl; or tetrazole, provided that whenm is zero, X is absent.

In one embodiment, the compounds of Formula II for use in the methods ofthe invention have one or more of the following characteristics: aninhibition constant (K_(i)) with regard to H1 receptor binding of lessthan 500 nM; a K_(i) with regard to off target binding to an off targetselected from M1, M2, M3, D1, D2, α1 and α2 that is greater than 1,000nm and/or more than 10 times greater than the K_(i) with regard to theH1 receptor; a nonREM peak time value that is greater than 55% nonREMsleep per hour by the third hour after the compound is administered to asubject; a cumulative total increase in nonREM sleep of not less than 20minutes for compound doses that produce maximum sleep consolidation; alongest sleep bout that is greater than 13 minutes in duration; netlongest sleep bout post treatment is greater than or equal to 3 minuteswhen adjusted using a baseline value obtained at least 24 hours prior toadministration of the compound to a subject; an average sleep bout thatis greater than 5 minutes at absolute peak; administration of thecompound to a subject does not produce appreciable amounts of reboundinsomnia; administration of the compound to a subject does notappreciably inhibit REM sleep; and administration of the compound to asubject does not disproportionately inhibit locomotor activity relativeto the normal effects of sleep.

In another embodiment, the compound of Formula II for use in the methodsof the invention has one or more of the following characteristics: aninhibition constant (K_(i)) with regard to H1 receptor binding of lessthan 300 nM; a K_(i) with regard to off target binding to an off targetselected from M1, M2, M3, D1, D2, α1 and α2 that is greater than 1 μm; anonREM peak time value that is greater than 55% nonREM sleep per hour bythe third hour after the compound is administered to a subject; acumulative total increase in nonREM sleep of not less than 20 minutesfor compound doses that produce maximum sleep consolidation; a longestsleep bout that is greater than 13 minutes in duration; net longestsleep bout post treatment is greater than or equal to 3 minutes whenadjusted using a baseline value obtained at least 24 hours prior toadministration of the compound to a subject; an average sleep bout thatis greater than 5 minutes at absolute peak; administration of thecompound to a subject does not produce appreciable amounts of reboundinsomnia; administration of the compound to a subject does notappreciably inhibit REM sleep; and administration of the compound to asubject does not disproportionately inhibit locomotor activity relativeto the normal effects of sleep.

In another embodiment, the compound of Formula II for use in the methodsof the invention has one or more of the following characteristics: aninhibition constant (K_(i)) with regard to H1 receptor binding of lessthan 150 nM; a K_(i) with regard to off target binding to an off targetselected from M1, M2, and M3, that is greater than 10 μM; a nonREM peaktime value that is greater than 55% nonREM sleep per hour by the thirdhour after the compound is administered to a subject; a cumulative totalincrease in nonREM sleep not less than 20 minutes for compound dosesthat produce maximum sleep consolidation; a longest sleep bout that isgreater than 17 minutes in duration; net longest sleep bout posttreatment is greater than or equal to 5 minutes when adjusted using abaseline value obtained at least 24 hours prior to administration of thecompound to a subject; an average sleep bout that is greater than 6minutes at absolute peak; administration of the compound to a subjectdoes not produce appreciable amounts of rebound insomnia; administrationof the compound to a subject does not appreciably inhibit REM sleep; andadministration of the compound to a subject does not disproportionatelyinhibit locomotor activity or motor tone relative to the normal effectsof sleep.

In one embodiment, Z is CO₂H or tetrazole. In one embodiment, o is zero.

In one embodiment, at least one of R₂, R₃, R₅, R₆, and at least one ofR₉-R₁₀, are not hydrogen when Z is COOH. In one embodiment, R₂, R₃, andR₅ are each hydrogen and R₆ is not hydrogen. In one embodiment, R₂, R₃,and R₅, are each hydrogen, and R₆ is methyl, ethyl, isopropyl, methoxy,methoxymethylene, or hydroxy.

In one embodiment, at least two of R₂, R₃, R₆, R₅ are not hydrogen, andthe remaining R₂, R₃, R₆, R₅ are hydrogen. In another embodiment, atleast three of R₂, R₃, R₆, R₅ are not hydrogen and the remaining R₂, R₃,R₆, R₅ are hydrogen. In one embodiment, R₂ is not hydrogen. In oneembodiment, R₃ is not hydrogen. In one embodiment, R₆ is not hydrogen.In one embodiment, R₅ is not hydrogen. In one embodiment, R₃ and R₆ arenot hydrogen. In another embodiment, R₂ and R₆ are not hydrogen. Inanother embodiment, R₃ and R₅ are not hydrogen.

In one embodiment, R₉ and R₁₀ are each methyl. In another embodiment, R₉and R₁₀ are each ethyl. In another embodiment, R₉ and R₁₀ are eachhydrogen.

In one embodiment, R₉ and R₁₀ and the carbon to which they are attachedare connected to form a spiro ring of size 3, 4, 5, 6, or 7. Forexample, in one embodiment, R₉ and R₁₀ and the carbon to which they areattached are connected to form a three-membered spiro (cyclopropyl)ring.

In one embodiment, R₉ and R₁₀ are methyl, R₆ is hydrogen or halogen, andthe remaining R₂, R₃, and R₅ are hydrogen. R₉ and R₁₀ are methyl, R₆ ishydrogen or halogen, and the remaining R₂, R₃, and R₅ are hydrogen, andZ is COOH.

In one embodiment, R₉ and R₁₀ are ethyl, R₆ is hydrogen or halogen, andthe remaining R₂, R₃, and R₅ are hydrogen. In another embodiment, R₉ andR₁₀ are ethyl, R₆ is hydrogen or halogen, and the remaining R₂, R₃, andR₅ are hydrogen, and Z is COOH.

In one embodiment, R₉ and R₁₀ and the carbon to which they are attachedare connected to form a three-membered spiro (cyclopropyl) ring. Inanother embodiment, R₉ and R₁₀ and the carbon to which they are attachedare connected to form a three-membered spiro (cyclopropyl) ring, R₆ ishydrogen or halogen, and the remaining R₂, R₃, and R₅ are hydrogen. Inanother embodiment, R₉ and R₁₀ and the carbon to which they are attachedare connected to form a three-membered spiro (cyclopropyl) ring, R₆ ishydrogen or halogen, and the remaining R₂, R₃, and R₅ are hydrogen, andZ is COOH.

In one embodiment, in the compound of Formula II used in the method ofthe invention, o is zero. In another embodiment, o is zero, and X isabsent. In another embodiment, o is zero, X is absent, and the sum of mand n is 2 or 3.

In one embodiment, the sleep modulation is, e.g., decreasing the time tosleep onset, increasing the average sleep bout length, and/or increasingthe maximum sleep bout length. In one embodiment, the sleep modulationtreats a sleep disorder.

Pharmaceutical compositions that include a compound of Formula II or apharmaceutically acceptable salt thereof are also used in the compoundsof modulating sleep in a subject. In one embodiment, the compound ofFormula II or a pharmaceutically acceptable salt thereof isco-administered with one or more additional therapies.

In another aspect, the invention provides a compound of modulating sleepin a subject by administering a therapeutically effective amount of acompound having the formula of Formula III:

or a pharmaceutically effective salt thereof, wherein m and n are,independently, 0, 1, 2, 3, or 4, X is absent, O or S; R₂, R₃, R₅, and R₆are, independently, selected from H, F, Cl, Br, CF₃, CH₃, OH, CH₂CH₃,CH(CH₃)₂, OCH₃, CH₂OCH₃, and CH₂OCH₂CH₃; R₉, and R₁₀, are,independently, H, C₁, C₂, C₃, C₄, C₅ straight chain alkyl; C₂, C₃, C₄,C₅, C₆ branched alkyl, or R₉, and R₁₀, together with the carbon to whichthey are attached, are connected to form a spiro ring of size 3, 4, 5,6, or 7; and Z is selected from CO₂H, CONHS(O)₂-alkyl,CONHS(O)₂-cycloalkyl, CONHS(O)₂-heteroalkyl, CONHS(O)₂-aryl,CONHS(O)₂-heteroaryl, and tetrazole; provided that when m is zero, X isabsent.

In one embodiment, the compounds of Formula III for use in the methodsof the invention have one or more of the following characteristics: aninhibition constant (K_(i)) with regard to H1 receptor binding of lessthan 500 nM; a K_(i) with regard to off target binding to an off targetselected from M1, M2, M3, D1, D2, α1 and α2 that is greater than 1,000nm and/or more than 10 times greater than the K_(i) with regard to theH1 receptor; a nonREM peak time value that is greater than 55% nonREMsleep per hour by the third hour after the compound is administered to asubject; a cumulative total increase in nonREM sleep of not less than 20minutes for compound doses that produce maximum sleep consolidation; alongest sleep bout that is greater than 13 minutes in duration; netlongest sleep bout post treatment is greater than or equal to 3 minuteswhen adjusted using a baseline value obtained at least 24 hours prior toadministration of the compound to a subject; an average sleep bout thatis greater than 5 minutes at absolute peak; administration of thecompound to a subject does not produce appreciable amounts of reboundinsomnia; administration of the compound to a subject does notappreciably inhibit REM sleep; and administration of the compound to asubject does not disproportionately inhibit locomotor activity relativeto the normal effects of sleep.

In another embodiment, the compound of Formula III for use in themethods of the invention has one or more of the followingcharacteristics: an inhibition constant (K_(i)) with regard to H1receptor binding of less than 300 nM; a K_(i) with regard to off targetbinding to an off target selected from M1, M2, M3, D1, D2, α1 and α2that is greater than 1 μm; a nonREM peak time value that is greater than55% nonREM sleep per hour by the third hour after the compound isadministered to a subject; a cumulative total increase in nonREM sleepof not less than 20 minutes for compound doses that produce maximumsleep consolidation; a longest sleep bout that is greater than 13minutes in duration; net longest sleep bout post treatment is greaterthan or equal to 3 minutes when adjusted using a baseline value obtainedat least 24 hours prior to administration of the compound to a subject;an average sleep bout that is greater than 5 minutes at absolute peak;administration of the compound to a subject does not produce appreciableamounts of rebound insomnia; administration of the compound to a subjectdoes not appreciably inhibit REM sleep; and administration of thecompound to a subject does not disproportionately inhibit locomotoractivity relative to the normal effects of sleep.

In another embodiment, the compound of Formula III for use in themethods of the invention has one or more of the followingcharacteristics: an inhibition constant (K_(i)) with regard to H1receptor binding of less than 150 nM; a K_(i) with regard to off targetbinding to an off target selected from M1, M2, and M3, that is greaterthan 10 μM; a nonREM peak time value that is greater than 55% nonREMsleep per hour by the third hour after the compound is administered to asubject; a cumulative total increase in nonREM sleep not less than 20minutes for compound doses that produce maximum sleep consolidation; alongest sleep bout that is greater than 17 minutes in duration; netlongest sleep bout post treatment is greater than or equal to 5 minuteswhen adjusted using a baseline value obtained at least 24 hours prior toadministration of the compound to a subject; an average sleep bout thatis greater than 6 minutes at absolute peak; administration of thecompound to a subject does not produce appreciable amounts of reboundinsomnia; administration of the compound to a subject does notappreciably inhibit REM sleep; and administration of the compound to asubject does not disproportionately inhibit locomotor activity or motortone relative to the normal effects of sleep.

In one embodiment, Z is CO₂H or tetrazole. In one embodiment, m is zero.In one embodiment, at least one of R₂, R₃, R₅, R₆, and at least one ofR₉-R₁₀, are not hydrogen when Z is COOH. In one embodiment, R₂, R₃, andR₅ are each hydrogen and R₆ is not hydrogen or halogen. In oneembodiment, R₂, R₃, and R₅, are each hydrogen, and R₆ is methyl, ethyl,isopropyl, methoxymethylene, methoxy, or hydroxy.

In one embodiment, R₂, R₃, and R₅ are each hydrogen and R₆ is nothydrogen or halogen. In one embodiment, R₂, R₃, and R₅, are eachhydrogen, and R₆ is methyl, ethyl, isopropyl, methoxymethylene, methoxy,or hydroxy.

In one embodiment, at least two of R₂, R₃, R₅, R₆ are not hydrogen, andthe remaining R₂, R₃, R₅, R₆ are hydrogen. In another embodiment, atleast three of R₂, R₃, R₅, R₆ are not hydrogen and the remaining R₂, R₃,R₅, R₆ are hydrogen. In one embodiment, R₂ is not hydrogen. In oneembodiment, R₃ is not hydrogen. In one embodiment, R₅ is not hydrogen.In one embodiment, R₆ is not hydrogen. In one embodiment, R₃ and R₆ arenot hydrogen. In another embodiment, R₂ and R₆ are not hydrogen. Inanother embodiment, R₃ and R₅ are not hydrogen.

In one embodiment, R₉ and R₁₀ are each methyl. In another embodiment, R₉and R₁₀ are each ethyl. In another embodiment, R₉ and R₁₀ are eachhydrogen.

In one embodiment, R₉ and R₁₀ and the carbon to which they are attachedare connected to form a spiro ring of size 3, 4, 5, 6, or 7. Forexample, in one embodiment, R₉ and R₁₀ and the carbon to which they areattached are connected to form a three-membered spiro (cyclopropyl)ring.

In one embodiment, R₉ and R₁₀ are methyl, R₆ is hydrogen, methyl, ethyl,or isopropyl, or halogen, and the remaining R₂, R₃, and R₅ are hydrogen.In another embodiment, R₉ and R₁₀ are methyl, R₆ is hydrogen, methyl,ethyl, isopropyl, or halogen, and the remaining R₂, R₃, and R₅ arehydrogen, and Z is COOH.

In one embodiment, R₉ and R₁₀ are ethyl, R₆ is hydrogen, methyl, ethyl,isopropyl, or halogen, and the remaining R₂, R₃, and R₅ are hydrogen. Inanother embodiment, R₉ and R₁₀ are ethyl, R₆ is hydrogen, methyl, ethyl,isopropyl, or halogen, and the remaining R₂, R₃, and R₅ are hydrogen,and Z is COOH.

In one embodiment, R₉ and R₁₀ and the carbon to which they are attachedare connected to form a three-membered spiro (cyclopropyl) ring. Inanother embodiment, R₉ and R₁₀ and the carbon to which they are attachedare connected to form a three-membered spiro (cyclopropyl) ring, R₆ ishydrogen, methyl or halogen, and the remaining R₂, R₃, and R₅ arehydrogen. In another embodiment, R₉ and R₁₀ and the carbon to which theyare attached are connected to form a three-membered spiro (cyclopropyl)ring, R₆ is hydrogen, methyl or halogen, and the remaining R₂, R₃, andR₅ are hydrogen, and Z is COOH.

In one embodiment, in the compound of Formula III used in the method ofthe invention, X is absent. In another embodiment, X is absent, and thesum of m and n is 2 or 3.

In one embodiment, the sleep modulation is, e.g., decreasing the time tosleep onset, increasing the average sleep bout length, and/or increasingthe maximum sleep bout length. In one embodiment, the sleep modulationtreats a sleep disorder.

Pharmaceutical compositions that include a compound of Formula III or apharmaceutically acceptable salt thereof are also used in the compoundsof modulating sleep according to the invention.

In another aspect, the invention provides a method of modulating sleepin a subject by administering a therapeutically effective amount of acompound having the formula of Formula IV:

or a pharmaceutically effective salt thereof wherein t is 1, 2, 3, or 4;R₂, R₃, R₅ and R₆ are, independently, H, F, Cl, Br, CF₃, CH₃, CH₂CH₃,CH(CH₃)₂, OH, OCH₃, CH₂OCH₃, or CH₂OCH₂CH₃; R₉-R₁₀ are H, CH₃, CH₂CH₃,or R₉ and R₁₀, together with the carbon to which they are attached, areconnected to form a spiro ring of size 3, 4, 5, 6, or 7; and Z isselected from CO₂H, CONHS(O)₂-alkyl, CONHS(O)₂-cycloalkyl,CONHS(O)₂-heteroalkyl, CONHS(O)₂-aryl, CONHS(O)₂-heteroaryl, ortetrazole.

Typical compounds have t=1 or 2.

In one embodiment, the compounds of Formula IV for use in the methods ofthe invention have one or more of the following characteristics: aninhibition constant (K_(i)) with regard to H1 receptor binding of lessthan 500 nM; a K_(i) with regard to off target binding to an off targetselected from M1, M2, M3, D1, D2, α1 and α2 that is greater than 1,000nm and/or more than 10 times greater than the K_(i) with regard to theH1 receptor; a nonREM peak time value that is greater than 55% nonREMsleep per hour by the third hour after the compound is administered to asubject; a cumulative total increase in nonREM sleep of not less than 20minutes for compound doses that produce maximum sleep consolidation; alongest sleep bout that is greater than 13 minutes in duration; netlongest sleep bout post treatment is greater than or equal to 3 minuteswhen adjusted using a baseline value obtained at least 24 hours prior toadministration of the compound to a subject; an average sleep bout thatis greater than 5 minutes at absolute peak; administration of thecompound to a subject does not produce appreciable amounts of reboundinsomnia; administration of the compound to a subject does notappreciably inhibit REM sleep; and administration of the compound to asubject does not disproportionately inhibit locomotor activity relativeto the normal effects of sleep.

In another embodiment, the compound of Formula IV for use in the methodsof the invention has one or more of the following characteristics: aninhibition constant (K_(i)) with regard to H1 receptor binding of lessthan 300 nM; a K_(i) with regard to off target binding to an off targetselected from M1, M2, M3, D1, D2, α1 and α2 that is greater than 1 μm; anonREM peak time value that is greater than 55% nonREM sleep per hour bythe third hour after the compound is administered to a subject; acumulative total increase in nonREM sleep of not less than 20 minutesfor compound doses that produce maximum sleep consolidation; a longestsleep bout that is greater than 13 minutes in duration; net longestsleep bout post treatment is greater than or equal to 3 minutes whenadjusted using a baseline value obtained at least 24 hours prior toadministration of the compound to a subject; an average sleep bout thatis greater than 5 minutes at absolute peak; administration of thecompound to a subject does not produce appreciable amounts of reboundinsomnia; administration of the compound to a subject does notappreciably inhibit REM sleep; and administration of the compound to asubject does not disproportionately inhibit locomotor activity relativeto the normal effects of sleep.

In another embodiment, the compound of Formula IV for use in the methodsof the invention has one or more of the following characteristics: aninhibition constant (K_(i)) with regard to H1 receptor binding of lessthan 150 nM; a K_(i) with regard to off target binding to an off targetselected from M1, M2, and M3, that is greater than 10 μM; a nonREM peaktime value that is greater than 55% nonREM sleep per hour by the thirdhour after the compound is administered to a subject; a cumulative totalincrease in nonREM sleep not less than 20 minutes for compound dosesthat produce maximum sleep consolidation; a longest sleep bout that isgreater than 17 minutes in duration; net longest sleep bout posttreatment is greater than or equal to 5 minutes when adjusted using abaseline value obtained at least 24 hours prior to administration of thecompound to a subject; an average sleep bout that is greater than 6minutes at absolute peak; administration of the compound to a subjectdoes not produce appreciable amounts of rebound insomnia; administrationof the compound to a subject does not appreciably inhibit REM sleep; andadministration of the compound to a subject does not disproportionatelyinhibit locomotor activity or motor tone relative to the normal effectsof sleep.

In one embodiment, Z is CO₂H or tetrazole. In another embodiment, when Zis COOH, at least one of R₂, R₃, R₅, and R₆, and at least one of R₉-R₁₀,are not hydrogen.

In one embodiment, R₉ and R₁₀ are each methyl. In another embodiment, R₉and R₁₀ are each ethyl. In one embodiment, R₉ and R₁₀ and the carbon towhich they are attached are connected to form a spiro ring of size fromthree to seven. For example, in one embodiment, R₉ and R₁₀ and thecarbon to which they are attached are connected to form a three-memberedspiro (cyclopropyl) ring.

In one embodiment, R₉ and R₁₀ are methyl; R₆ is hydrogen, methyl, orhalogen; and R₂, R₃ and R₅ are hydrogen. In another embodiment, R₉ andR₁₀ are methyl; R₆ is hydrogen, methyl, or halogen; and R₂, R₃ and R₅are hydrogen; and Z is COOH.

In one embodiment, R₉ and R₁₀ are ethyl; R₆ is hydrogen, methyl, ethyl,isopropyl, or halogen; and R₂, R₃ and R₅ are hydrogen. In anotherembodiment, R₉ and R₁₀ are methyl; R₆ is hydrogen, methyl, ethyl,isopropyl, or halogen; and R₂, R₃ and R₅ are hydrogen; and Z is COOH.

In one embodiment, R₉ and R₁₀ and the carbon to which they are attachedare connected to form a three-membered spiro (cyclopropyl) ring. Inanother embodiment, R₉ and R₁₀ and the carbon to which they are attachedare connected to form a three-membered spiro (cyclopropyl) ring, R₆ ishydrogen, methyl, or halogen; and R₂, R₃ and R₅ are hydrogen. In anotherembodiment, R₉ and R₁₀ and the carbon to which they are attached areconnected to form a three-membered spiro (cyclopropyl) ring, R₆ ishydrogen, methyl, or halogen; and R₂, R₃ and R₅ are hydrogen; and Z isCOOH.

In one embodiment, the sleep modulation is selected from decreasing thetime to sleep onset, increasing the average sleep bout length, andincreasing the maximum sleep bout length. In one embodiment, the sleepmodulation treats a sleep disorder.

Pharmaceutical compositions that include a compound of Formula IV or apharmaceutically acceptable salt thereof are also used in the compoundsof modulating sleep according to the invention.

In one embodiment, the compound of Formula IV used in the methods of theinvention is IVa, IVb, IVc, IVd, or IVe.

For example, when R₉ and R₁₀ are methyl, compounds have the generalformula IVa:

when R₉ and R₁₀ are connected to form a 3 membered spiro ring(cyclopropyl), compounds have the general formula IVb:

when R₉ and R₁₀ are ethyl, compounds have the general formula IVc:

when R₉ and R₁₀ are ethyl, and the C1 carbons are connected to form a 3membered spiro ring (cyclopropyl), compounds have the general formulaIVd:

and when and R₉ and R₁₀ are hydrogen, compounds have the general formulaIVe:

In another aspect, the invention provides a compound according toFormula I:

or a pharmaceutically effective salt thereof, wherein: m, n, o, p, qare, independently, an integer from 0, 1, 2, 3, 4, 5, or 6; A and B are,independently, O, S, NR₇, or C(R₈)₂; X and Y are, independently, absent,O, S, C(O), SO or SO₂; R₁, R₂, R₃, R₄, R₅, R₆, R₇, and R₈ are,independently, H, F, Cl, Br, OH, CH₃, C₂, C₃, C₄, C₅, C₆ straight chainalkyl, C₃, C₄, C₅, C₆ branched alkyl, C₃, C₄, C₅, C₆, C₇ cycloalkyl, C₃,C₄, C₅, C₆, C₇ heterocyclyl, OCH₃, OCF₃, CH₂OCH₃, CH₂CH₂OCH₃,CH₂OCH₂CH₃, C₁, C₂, C₃, C₄, C₅, C₆ hydroxyalkyl, or C₁, C₂, C₃, C₄, C₅,C₆ alkoxy; any hydrogen in the CH₂ groups in the linker is optionallysubstituted with H, F, Cl, OH, Br, CF₃, CH₃, C₂, C₃, C₄, C₅, C₆ straightchain alkyl, C₃, C₄, C₅, C₆ branched alkyl, C₃, C₄, C₅, C₆, C₇cycloalkyl, C₃, C₄, C₅, C₆, C₇ heterocyclyl, OCH₃, OCF₃, CH₂OCH₃,CH₂CH₂OCH₃, CH₂OCH₂CH₃, C₁-C₆ hydroxyalkyl; or C₁, C₂, C₃, C₄, C₅, C₆alkoxy; R₉, R₁₀, R₁₁, and R₁₂ are, independently, H, C₁, C₂, C₃, C₄, C₅straight chain alkyl, C₂, C₃, C₄, C₅, C₆ branched alkyl, or R₉ and R₁₀together with the carbon to which they are attached are absent or areconnected to form a spiro ring of size 3, 4, 5, 6, or 7, or R₁₁ and R₁₂together with the carbon to which they are attached are connected toform a spiro ring of size 3, 4, 5, 6, or 7, or substituents on twodifferent carbon atoms are connected to form a ring of size 3, 4, 5, 6,or 7; Z is selected from CO₂H, CO₂R₁₃, where R₁₃ is C₁, C₂, C₃, C₄, C₅,C₆ alkyl, CONR₁₄R₁₅, where R₁₄ and R₁₅ are, independently, hydrogen orlower alkyl, CONHS(O)₂-alkyl, CONHS(O)₂-cycloalkyl,CONHS(O)₂-heteroalkyl, CONHS(O)₂-aryl, CONHS(O)₂-heteroaryl,S(O)₂NHCO-alkyl, S(O)₂NHCO-cycloalkyl, S(O)₂NHCO-heteroalkyl,S(O)₂NHCO-aryl, S(O)₂NHCO-heteroaryl, CONHS(O)₂N-alkyl,CONHS(O)₂N-cycloalkyl, CONHS(O)₂N-heteroalkyl, CONHS(O)₂N-aryl,CONHS(O)₂N-heteroaryl, SO₃H, SO₂H, S(O)NHCO-alkyl, S(O)NHCO-aryl,S(O)NHCO-heteroaryl, P(O)(OH)₂, P(O)OH, P

provided that when m is zero, X is absent.

In one embodiment, the compound is Compound 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63,64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81,82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99,100, 101, 102, 103, 104, 105, or 106.

In one embodiment, the compound is Compound 46:

In one embodiment, Z is CO₂H, tetrazole, a sulfonamide, or a sulfamide.In another embodiment, when Z is COOH, at least one of R₁-R₆, and atleast one of R₉-R₁₂, are not hydrogen.

In one embodiment, R₆ is not H or halogen. In another embodiment, R₁-R₅are each hydrogen and R₆ is not hydrogen.

In one embodiment, at least one of R₁-R₆ is not hydrogen, and theremaining R₁-R₆ are hydrogen. In another embodiment, at least two ofR₁-R₆ are not hydrogen, and the remaining R₁-R₆ are hydrogen. In anotherembodiment, at least three of R₁-R₆ are not hydrogen and the remainingR₁-R₆ are hydrogen. In another embodiment, at least four of R₁-R₆ arenot hydrogen and the remaining R₁-R₆ are hydrogen. In one embodiment, R₂is not hydrogen. In one embodiment, R₃ is not hydrogen. In oneembodiment, R₆ is not hydrogen. In one embodiment, R₅ is not hydrogen.In one embodiment, R₃ and R₆ are not hydrogen. In another embodiment, R₂and R₆ are not hydrogen. In another embodiment, R₃ and R₅ are nothydrogen. In another embodiment, R₂ and R₅ are not hydrogen. In anotherembodiment, R₂ and R₃ are not hydrogen. In another embodiment, R₆ and R₅are not hydrogen.

In one embodiment, at least one of R₁-R₆ is methyl, ethyl, isopropyl,methoxymethylene, chloro, fluoro, bromo, hydroxy, or methoxy. In anotherembodiment, R₂ is methyl, methoxymethylene, chloro, fluoro, bromo,hydroxy, or methoxy. In another embodiment, R₃ is methyl,methoxymethylene, chloro, fluoro, bromo, hydroxy, or methoxy. In anotherembodiment, R₅ is methyl, methoxymethylene, chloro, fluoro, bromo,hydroxy, or methoxy. In another embodiment, R₆ is methyl, ethyl,isopropyl, methoxymethylene, chloro, fluoro, bromo, hydroxy, or methoxy.

In another embodiment, at least two of R₁-R₆ are methyl, ethyl,isopropyl, methoxymethylene, chloro, fluoro, bromo, hydroxy, or methoxy.In another embodiment, at least two of R₁-R₆ are methyl, ethyl,isopropyl, methoxymethylene, chloro, fluoro, bromo, hydroxy, or methoxy;and Z is COOH. In another embodiment, at least two of R₁-R₆ are methyl,ethyl, isopropyl, methoxymethylene, chloro, fluoro, bromo, hydroxy, ormethoxy; R₉ and R₁₀ are hydrogen; and Z is COOH.

In one embodiment, R₃ and R₆ are both methyl, methoxy, methoxymethylene,methoxymethylene, hydroxy, chloro, fluoro, or bromo, and the remainingR₁-R₂, R₄-R₅ are hydrogen. In another embodiment, R₂ and R₆ are bothmethyl, ethyl, isopropyl, methoxy, methoxymethylene, hydroxy, chloro,fluoro, or bromo, and the remaining R₁ and R₃-R₅ are hydrogen. In oneembodiment, R₃ and R₅ are both methyl, methoxy, methoxymethylene,hydroxy, chloro, fluoro, or bromo, and the remaining R₁-R₂, R₄ and R₆are hydrogen. In one embodiment, R₂ and R₅ are both methyl, methoxy,hydroxy, methoxymethylene, chloro, fluoro, or bromo, and the remainingR₁, R₃-R₄, and R₆ are hydrogen. In one embodiment, R₂ and R₃ are bothmethyl, methoxy, hydroxy, methoxymethylene, chloro, fluoro, or bromo,and the remaining R₁ and R₄-R₆ are hydrogen.

In one embodiment, R₆ is methyl. In one embodiment, R₆ is methyl and R₂or R₃ is methyl, methoxy, methoxymethylene, chloro, fluoro, or bromo. Inanother embodiment, R₆ is fluoro and R₂ or R₃ is methylmethoxymethylene, or methoxy. In one embodiment, R₆ is methoxy. In oneembodiment, R₆ is methoxy and R₂ or R₃ is methyl, methoxy,methoxymethylene, hydroxy, chloro, fluoro, or bromo. In anotherembodiment, R₆ is fluoro and R₂ or R₃ is methoxy.

In one embodiment, R₉ and R₁₀, together with the carbon to which theyare attached, are connected to form a spiro ring of size 3, 4, 5, 6, or7. In one embodiment, R₉ and R₁₀, together with the carbon to which theyare attached are absent, and R₁₁ and R₁₂, together with the carbon towhich they are attached, are connected to form a spiro ring of size 3,4, 5, 6, or 7. For example, R₉ and R₁₀ together with the carbon to whichthey are attached or R₁₁ and R₁₂ together with the carbon to which theyare attached, are connected to form a spiro 3-membered cyclopropyl ring.

In one embodiment, R₉ and R₁₀ are hydrogen.

In one embodiment, R₉ and R₁₀ are methyl. In another embodiment, R₉ andR₁₀ are methyl, R₆ is methyl, ethyl, isopropyl, hydrogen or halogen, andR₁-R₅ are hydrogen. In another embodiment, R₉ and R₁₀ are methyl, R₆ ismethyl, ethyl, isopropyl, hydrogen or halogen, R₁-R₅ are hydrogen, and Zis COOH.

In one embodiment, R₉ and R₁₀ are ethyl. In another embodiment, R₉ andR₁₀ are ethyl, R₆ is methyl, hydrogen or halogen, and R₁-R₅ arehydrogen. In another embodiment, R₉ and R₁₀ are ethyl, R₆ is methyl,hydrogen or halogen, R₁-R₅ are hydrogen, and Z is COOH.

In one embodiment, R₉ and R₁₀ and the carbon to which they are attachedare connected to form a three-membered spiro (cyclopropyl) ring. Inanother embodiment, R₉ and R₁₀ and the carbon to which they are attachedare connected to form a three-membered spiro (cyclopropyl) ring, R₆ ismethyl, hydrogen or halogen, and R₁-R₅ are hydrogen. In anotherembodiment, R₉ and R₁₀ and the carbon to which they are attached areconnected to form a three-membered spiro (cyclopropyl) ring, R₆ ismethyl, hydrogen or halogen, and R₁-R₅ are hydrogen and Z is COOH.

In another embodiment, R₉ and R₁₀ are methyl, R₆ is methoxy, and R₁-R₅are hydrogen. In another embodiment, R₉ and R₁₀ are methyl, R₆ ismethoxy, R₁-R₅ are hydrogen, and Z is COOH.

In another embodiment, R₉ and R₁₀ are methyl, R₆ is methoxymethylene,and R₁-R₅ are hydrogen. In another embodiment, R₉ and R₁₀ are methyl, R₆is methoxymethylene, R₁-R₅ are hydrogen, and Z is COOH.

In another embodiment, R₉ and R₁₀ are ethyl, R₆ is methoxy, and R₁-R₅are hydrogen. In another embodiment, R₉ and R₁₀ are ethyl, R₆ ismethoxy, R₁-R₅ are hydrogen, and Z is COOH.

In another embodiment, R₉ and R₁₀ and the carbon to which they areattached are connected to form a three-membered spiro (cyclopropyl)ring, R₆ is methoxy, and R₁-R₅ are hydrogen. In another embodiment, R₉and R₁₀ and the carbon to which they are attached are connected to forma three-membered spiro (cyclopropyl) ring, R₆ is methoxy, and R₁-R₅ arehydrogen and Z is COOH.

In one embodiment R₉ and R₁₀ together with the carbon to which they areattached are absent.

In one embodiment, R₁₁ and R₁₂ are methyl. In another embodiment, R₁₁and R₁₂ are methyl, R₆ is hydrogen or halogen, and R₁-R₅ are hydrogen.In another embodiment, R₁₁ and R₁₂ are methyl, R₆ is hydrogen orhalogen, R₁-R₅, are hydrogen, and Z is COOH.

In one embodiment, R₁₁ and R₁₂ are ethyl. In another embodiment, R₁₁ andR₁₂ are ethyl, R₆ is hydrogen or halogen, and R₁-R₅ are hydrogen. Inanother embodiment, R₁₁ and R₁₂ are ethyl, R₆ is hydrogen or halogen,R₁-R₅ are hydrogen, and Z is COOH.

In one embodiment, R₁₁ and R₁₂ and the carbon to which they are attachedare connected to form a three-membered spiro (cyclopropyl) ring. Inanother embodiment, R₁₁ and R₁₂ and the carbon to which they areattached are connected to form a three-membered spiro (cyclopropyl)ring, R₆ is hydrogen or halogen, and R₁-R₅ are hydrogen. In anotherembodiment, R₁₁ and R₁₂ and the carbon to which they are attached areconnected to form a three-membered spiro (cyclopropyl) ring, R₆ ishydrogen or halogen, and R₁-R₅ are hydrogen and Z is COOH.

In one embodiment, R₁₁ and R₁₂ are methyl and R₆ is methoxy. In anotherembodiment, R₁₁ and R₁₂ are methyl, R₆ is methoxy, and R₁-R₅ arehydrogen. In another embodiment, R₁₁ and R₁₂ are methyl, R₆ is methoxy,R₁-R₅ are hydrogen, and Z is COOH.

In one embodiment, R₁₁ and R₁₂ are ethyl and R₆ is methoxy. In anotherembodiment, R₁₁ and R₁₂ are ethyl, R₆ is methoxy, and R₁-R₅ arehydrogen. In another embodiment, R₁₁ and R₁₂ are ethyl, R₆ is methoxy,R₁-R₅ are hydrogen, and Z is COOH.

In one embodiment, R₁₁ and R₁₂ and the carbon to which they are attachedare connected to form a three-membered spiro (cyclopropyl) ring and R₆is methoxy. In another embodiment, R₁₁ and R₁₂ and the carbon to whichthey are attached are connected to form a three-membered spiro(cyclopropyl) ring, R₆ is methoxy, and R₁-R₅ are hydrogen. In anotherembodiment, R₁₁ and R₁₂ and the carbon to which they are attached areconnected to form a three-membered spiro (cyclopropyl) ring, R₆ ismethoxy, and R₁-R₅ are hydrogen and Z is COOH.

In one embodiment, q is zero. In another embodiment, q is zero, and R₉and R₁₀ together with the carbon to which they are attached are absent.In another embodiment, q is zero, R₉ and R₁₀ together with the carbon towhich they are attached are absent, X and Y are absent. In anotherembodiment, q is zero, R₉ and R₁₀ together with the carbon to which theyare attached are absent, X and Y are absent, and the sum of m, n, o, andp is 2 or 3.

Pharmaceutical compositions that include a compound of Formula I or apharmaceutically acceptable salt thereof are also used in the methods ofmodulating sleep according to the invention.

In another aspect, the present invention provides a compound having theformula of Formula II:

or a pharmaceutically effective salt thereof, wherein m, n, and o are,independently, 0, 1, 2, 3, 4, 5, or 6; X is absent, O, S, C(O), SO orSO₂; R₂, R₃, R₅, and R₆ are, independently selected from H, F, Cl, Br,CF₃, CH₃, CH₂CH₃, CH(CH₃)₂, cyclopropyl, OH, OCH₃, OCF₃, CH₂OCH₃ andCH₂OCH₂CH₃; R₉, and R₁₀, are, independently, H, C₁, C₂, C₃, C₄, C₅straight chain alkyl; C₂, C₃, C₄, C₅, C₆ branched alkyl, or R₉ and R₁₀together with the carbon to which they are attached, are connected toform a spiro ring of size 3, 4, 5, 6, or 7; and Z is COOH, COOR₁₃, whereR₁₃ is C₁, C₂, C₃, C₄, C₅, C₆ alkyl, CONHS(O)₂-alkyl,CONHS(O)₂-heteroalkyl, CONHS(O)₂-aryl, CONHS(O)₂-heteroaryl,S(O)₂NHCO-alkyl, S(O)₂NHCO-heteroalkyl, S(O)₂NHCO-aryl,S(O)₂NHCO-heteroaryl, CONHS(O)₂N-alkyl; CONHS(O)₂N-heteroalkyl;CONHS(O)₂N-aryl; CONHS(O)₂N-heteroaryl; or tetrazole, provided that whenm is zero, X is absent.

In one embodiment, Z is CO₂H or tetrazole. In another embodiment, when Zis COOH, at least one of R₂, R₃, R₅, and R₆, and at least one of R₉-R₁₀,are not hydrogen. In one embodiment, o is zero.

In one embodiment, at least one of R₂, R₃, R₅, R₆, and at least one ofR₉-R₁₀, are not hydrogen when Z is COOH. In one embodiment, R₂, R₃, andR₅ are each hydrogen and R₆ is not hydrogen or halogen. In oneembodiment, R₂, R₃, and R₅, are each hydrogen, and R₆ is methyl, ethyl,isopropyl, methoxy, or hydroxy.

In one embodiment, at least two of R₂, R₃, R₅, R₆ are not hydrogen, andthe remaining R₂, R₃, R₅, R₆ are hydrogen. In another embodiment, atleast three of R₂, R₃, R₅, R₆ are not hydrogen and the remaining R₂, R₃,R₅, R₆ are hydrogen. In one embodiment, R₂ is not hydrogen. In oneembodiment, R₃ is not hydrogen. In one embodiment, R₅ is not hydrogen.In one embodiment, R₆ is not hydrogen. In one embodiment, R₃ and R₆ arenot hydrogen. In another embodiment, R₂ and R₆ are not hydrogen. Inanother embodiment, R₃ and R₅ are not hydrogen.

In one embodiment, R₉ and R₁₀ are each methyl. In another embodiment, R₉and R₁₀ are each ethyl. In another embodiment, R₉ and R₁₀ are eachhydrogen.

In one embodiment, R₉ and R₁₀ and the carbon to which they are attachedare connected to form a spiro ring of size 3, 4, 5, 6, or 7. Forexample, in one embodiment, R₉ and R₁₀ and the carbon to which they areattached are connected to form a three-membered spiro (cyclopropyl)ring.

In one embodiment, R₉ and R₁₀ are methyl, R₆ is hydrogen or halogen, andthe remaining R₂, R₃, and R₅ are hydrogen. R₉ and R₁₀ are methyl, R₆ ishydrogen or halogen, and the remaining R₂, R₃, and R₅ are hydrogen, andZ is COOH.

In one embodiment, R₉ and R₁₀ are ethyl, R₆ is hydrogen or halogen, andthe remaining R₂, R₃, and R₅ are hydrogen. In another embodiment, R₉ andR₁₀ are ethyl, R₆ is hydrogen or halogen, and the remaining R₂, R₃, andR₅ are hydrogen, and Z is COOH.

In one embodiment, R₉ and R₁₀ and the carbon to which they are attachedare connected to form a three-membered spiro (cyclopropyl) ring. Inanother embodiment, R₉ and R₁₀ and the carbon to which they are attachedare connected to form a three-membered spiro (cyclopropyl) ring, R₆ ishydrogen or halogen, and the remaining R₂, R₃, and R₅ are hydrogen. Inanother embodiment, R₉ and R₁₀ and the carbon to which they are attachedare connected to form a three-membered spiro (cyclopropyl) ring, R₆ ishydrogen or halogen, and the remaining R₂, R₃, and R₅ are hydrogen, andZ is COOH.

In one embodiment, in the compound of Formula II, o is zero. In anotherembodiment, o is zero, and X is absent. In another embodiment, o iszero, X is absent, and the sum of m and n is 2 or 3.

Pharmaceutical compositions that include a compound of Formula II or apharmaceutically acceptable salt thereof are also used in the methods ofmodulating sleep according to the invention.

In another aspect, the invention provides a compound having the formulaof Formula III:

or a pharmaceutically effective salt thereof, wherein m and n are,independently, 0, 1, 2, 3, or 4, X is absent, O, or S; R₂, R₃, R₅, andR₆ are, independently, selected from H, F, Cl, Br, CF₃, CH₃, OH, CH₂CH₃,CH(CH₃)₂, OCH₃, CH₂OCH₃, and CH₂OCH₂CH₃; R₉, and R₁₀, are,independently, H, C₁, C₂, C₃, C₄, C₅ straight chain alkyl; C₂, C₃, C₄,C₅, C₆ branched alkyl, or R₉, and R₁₀, together with the carbon to whichthey are attached, are connected to form a spiro ring of size 3, 4, 5,6, or 7; and Z is selected from CO₂H, CONHS(O)₂-alkyl,CONHS(O)₂-cycloalkyl, CONHS(O)₂-heteroalkyl, CONHS(O)₂-aryl,CONHS(O)₂-heteroaryl, and tetrazole; provided that when m is zero, X isabsent.

In one embodiment, Z is CO₂H or tetrazole. In one embodiment, m is zero.In one embodiment, at least one of R₂, R₃, R₅, R₆, and at least one ofR₉-R₁₀, are not hydrogen when Z is COOH. In one embodiment, R₂, R₃, andR₅ are each hydrogen and R₆ is not hydrogen or halogen. In oneembodiment, R₂, R₃, and R₅, are each hydrogen, and R₆ is methyl,methoxy, or hydroxy.

In one embodiment, R₂, R₃, and R₅ are each hydrogen and R₆ is nothydrogen. In one embodiment, R₂, R₃, and R₅, are each hydrogen, and R₆is methyl, ethyl, isopropyl, methoxymethylene, methoxy, or hydroxy.

In one embodiment, at least two of R₂, R₃, R₅, R₆ are not hydrogen, andthe remaining R₂, R₃, R₅, R₆ are hydrogen. In another embodiment, atleast three of R₂, R₃, R₅, R₆ are not hydrogen and the remaining R₂, R₃,R₅, R₆ are hydrogen. In one embodiment, R₂ is not hydrogen. In oneembodiment, R₃ is not hydrogen. In one embodiment, R₅ is not hydrogen.In one embodiment, R₆ is not hydrogen. In one embodiment, R₃ and R₆ arenot hydrogen. In another embodiment, R₂ and R₆ are not hydrogen. Inanother embodiment, R₃ and R₅ are not hydrogen.

In one embodiment, R₉ and R₁₀ are each methyl. In another embodiment, R₉and R₁₀ are each ethyl. In another embodiment, R₉ and R₁₀ are eachhydrogen.

In one embodiment, R₉ and R₁₀ and the carbon to which they are attachedare connected to form a spiro ring of size 3, 4, 5, 6, or 7. Forexample, in one embodiment, R₉ and R₁₀ and the carbon to which they areattached are connected to form a three-membered spiro (cyclopropyl)ring.

In one embodiment, R₉ and R₁₀ are methyl, R₆ is hydrogen or halogen, andthe remaining R₂, R₃, and R₅ are hydrogen. In another embodiment, R₉ andR₁₀ are methyl, R₆ is hydrogen or halogen, and the remaining R₂, R₃, andR₅ are hydrogen, and Z is COOH.

In one embodiment, R₉ and R₁₀ are ethyl, R₆ is hydrogen or halogen, andthe remaining R₂, R₃, and R₅ are hydrogen. In another embodiment, R₉ andR₁₀ are ethyl, R₆ is hydrogen or halogen, and the remaining R₂, R₃, andR₅ are hydrogen, and Z is COOH.

In one embodiment, R₉ and R₁₀ and the carbon to which they are attachedare connected to form a three-membered spiro (cyclopropyl) ring. Inanother embodiment, R₉ and R₁₀ and the carbon to which they are attachedare connected to form a three-membered spiro (cyclopropyl) ring, R₆ ishydrogen or halogen, and the remaining R₂, R₃, and R₅ are hydrogen. Inanother embodiment, R₉ and R₁₀ and the carbon to which they are attachedare connected to form a three-membered spiro (cyclopropyl) ring, R₆ ishydrogen or halogen, and the remaining R₂, R₃, and R₅ are hydrogen, andZ is COOH.

In one embodiment, in the compound of Formula III, X is absent. Inanother embodiment, X is absent, and the sum of m and n is 2 or 3.

Pharmaceutical compositions that include a compound of Formula III or apharmaceutically acceptable salt thereof are also used in the methods ofmodulating sleep according to the invention.

In another aspect, the invention provides a compound having the formulaof Formula Iv:

or a pharmaceutically effective salt thereof wherein t is 1, 2, 3, or 4;R₂, R₃, R₅ and R₆ are, independently, H, F, Cl, Br, CF₃, CH₃, CH₂CH₃,CH(CH₃)₂, OH, OCH₃, CH₂OCH₃, or CH₂OCH₂CH₃; R₉-R₁₀ are H, CH₃, CH₂CH₃,or R₉ and R₁₀, together with the carbon to which they are attached, areconnected to form a spiro ring of size 3, 4, 5, 6, or 7; and Z isselected from CO₂H, CONHS(O)₂-alkyl, CONHS(O)₂-cycloalkyl,CONHS(O)₂-heteroalkyl, and tetrazole.

Typical compounds have t=1 or 2.

Pharmaceutical compositions that include a compound of Formula IV or apharmaceutically acceptable salt thereof are also used in the methods ofmodulating sleep according to the invention.

In one embodiment, Z is CO₂H, sulfonamide, sulfamide, or tetrazole. Inanother embodiment, when Z is COOH, at least one of R₂, R₃, and R₅, andat least one of R₉-R₁₀, are not hydrogen.

In one embodiment, R₉ and R₁₀ are each methyl. In another embodiment, R₉and R₁₀ are each ethyl. In one embodiment, R₉ and R₁₀ and the carbon towhich they are attached are connected to form a spiro ring of size 3, 4,5, 6, or 7. For example, in one embodiment, R₉ and R₁₀ and the carbon towhich they are attached are connected to form a three-membered spiro(cyclopropyl) ring.

In one embodiment, R₉ and R₁₀ are methyl; R₆ is hydrogen, methyl, ethyl,isopropyl, or halogen; and R₂, R₃ and R₅ are hydrogen. In anotherembodiment, R₉ and R₁₀ are methyl; R₆ is hydrogen or halogen; and R₂, R₃and R₅ are hydrogen; and Z is COOH.

In one embodiment, R₉ and R₁₀ are ethyl; R₆ is hydrogen, methyl, ethyl,isopropyl, or halogen; and R₂, R₃ and R₅ are hydrogen. In anotherembodiment, R₉ and R₁₀ are methyl; R₆ is hydrogen or halogen; and R₂, R₃and R₅ are hydrogen; and Z is COOH.

In one embodiment, R₉ and R₁₀ and the carbon to which they are attachedare connected to form a three-membered spiro (cyclopropyl) ring. Inanother embodiment, R₉ and R₁₀ and the carbon to which they are attachedare connected to form a three-membered spiro (cyclopropyl) ring, R₆ ishydrogen, methyl or halogen; and R₂, R₃ and R₅ are hydrogen. In anotherembodiment, R₉ and R₁₀ and the carbon to which they are attached areconnected to form a three-membered spiro (cyclopropyl) ring, R₆ ishydrogen, methyl or halogen; and R₂, R₃ and R₅ are hydrogen; and Z isCOOH.

Pharmaceutical compositions that include a compound of Formula IV or apharmaceutically acceptable salt thereof are also used in the methods ofmodulating sleep according to the invention.

In one embodiment, the compound of Formula IV is IVa, IVb, IVc, IVd orIVe.

For example, when R₉ and R₁₀ are methyl, compounds have the generalformula IVa:

when R₉ and R₁₀ are connected to form a 3 membered spiro ring(cyclopropyl), compounds have the general formula IVb:

when R₉ and R₁₀ are ethyl, compounds have the general formula IVc:

when R₉ and R₁₀ are ethyl, and the C1 carbons are connected to form a 3membered spiro ring (cyclopropyl), compounds have the general formulaIVd:

and when and R₉ and R₁₀ are hydrogen, compounds have the general formulaIVe:

Some representative compounds of the invention include the compoundslisted in Table 1:

TABLE 1 Olanzapine derivatives

Cmpd # A R₂ R₃ R₅ R₆ R₉, R₁₀ T Size Ring** Z 1 NH H H H H CH₃ 1 noneCOOH 2 NH H H H H CH₃ 1 3 COOH 3 NH H H H H CH₃ 2 none COOH 4 NH H H F HCH₃ 1 none COOH 5 NH H H Cl H CH₃ 1 none COOH 6 NH H H Cl H CH₃ 2 noneCOOH 7 NH H H Cl H CH₃ 1 3 COOH 8 NH H H Br H CH₃ 1 none COOH 9 NH H HBr H CH₃ 1 3 COOH 10 NH H H CH₃ H CH₃ 1 none COOH 11 NH H H CH₃ H CH₃ 2none COOH 12 NH H H OCH₃ H CH₃ 1 none COOH 13 NH H H OCH₃ H CH₃ 2 noneCOOH 14 NH H H OH H CH₃ 1 none COOH 15 NH H F H H CH₃ 1 none COOH 16 NHH F CH₃ H CH₃ 1 none COOH 17 NH H Br H H CH₃ 1 none COOH 18 NH H Br Br HCH₃ 1 none COOH 19 NH H CH₃ H H CH₃ 1 none COOH 20 NH H CH₃ CH₃ H CH₃ 1none COOH 21 NH H OCH₃ H H CH₃ 1 none COOH 22 NH H OCH₃ F H CH₃ 1 noneCOOH 23 NH H OCH₃ OCH₃ H CH₃ 1 none COOH 24 NH H OH H H CH₃ 1 none COOH25 NH H OH OH H CH₃ 1 none COOH 26 NH F H H H CH₃ 1 none COOH 27 NH F HCH₃ H CH₃ 1 none COOH 28 NH Br H H H CH₃ 1 none COOH 29 NH Br H Br H CH₃1 none COOH 30 NH CH₃ H H H CH₃ 1 none COOH 31 NH CH₃ H CH₃ H CH₃ 1 noneCOOH 32 NH OCH₃ H H H CH₃ 1 none COOH 33 NH OCH₃ H F H CH₃ 1 none COOH34 NH OCH₃ H CH₃ H CH₃ 1 none COOH 35 NH OCH3 H OCH₃ H CH₃ 1 none COOH36 NH OCH₃ CH₃ H H CH₃ 1 none COOH 37 NH OH H H H CH₃ 1 none COOH 38 NHOH H OH H CH₃ 1 none COOH 39 NH H H H OCH₃ CH₃ 1 none COOH 40 NH H H H HCH₃ 1 none CONHSO₂CH₃ 41 NH H H H H CH₃ 1 none tetrazole 42 NH H OCH₃ HOCH₃ CH₃ 1 none COOH 43 NH H OCH₃ CH₃ H CH₃ 2 none COOH 44 NH H Br H CH₃CH₃ 1 none COOH 45 NH H H H Br CH₃ 1 none COOH 46 NH H H H CH₃ CH₃ 1none COOH 47 NH H F Br H CH₃ 1 none COOH 48 NH H F OCH₃ H CH₃ 1 noneCOOH 49 NH H Br H Br CH₃ 1 none COOH 50 NH H Br CH₃ H CH₃ 1 none COOH 51NH H Br OCH₃ H CH₃ 1 none COOH 52 NH H CH₃ H CH₃ CH₃ 1 none COOH 53 NH HCH₃ F H CH₃ 1 none COOH 54 NH H CH₃ OCH₃ H CH₃ 1 none COOH 55 NH H OCH₃H CH₃ CH₃ 1 none COOH 56 NH H OCH₃ CH₃ H CH₃ 1 none COOH 57 NH CH₃ H BrH CH₃ 1 none COOH 58 NH CH₃ H OCH₃ H CH₃ 1 none COOH 59 NH H H CH₃ H H 1none COOH 60 NH H H CH₃ H H 2 none COOH 61 NH H H OCH₃ H H 1 none COOH62 NH H H OCH₃ H H 2 none COOH 63 NH H H OCH₃ H CH₃ 1 3 COOH 64 NH H BrBr H CH₃ 2 none COOH 65 NH H CH₃ Br H CH₃ 1 none COOH 66 NH H OH OH HCH₃ 2 none COOH 67 NH H OCH₃ H F CH₃ 1 none COOH 68 NH H CH₃ H F CH₃ 1none COOH 69 NH H H H F CH₃ 1 none COOH 70 NH H H OCH₃ H CH₃ 1 nonetetrazole 71 NH H H OCH₃ H CH₃ 1 none CONHSO₂CH₃ 72 NH Br H OCH₃ H CH₃ 1none COOH 73 NH OH H OCH₃ H CH₃ 1 none COOH 74 NH H H OCH₃ H H 1 nonetetrazole 75 NH H H OCH₃ H H 1 none CONHSO₂CH₃ 76 NH H H OCH₃ H H 2 nonetetrazole 77 NH H H OCH₃ H H 2 none CONHSO₂CH₃ 78 NH H H OCH₃ H CH₃ 2none tetrazole 79 NH H H OCH₃ H CH₃ 2 none CONHSO₂CH₃ 80 NH H H OCH₃ HCH₃ 1 3 tetrazole 81 NH H H OCH₃ H CH₃ 1 3 CONHSO₂CH₃ 82 NH H H OCH₃ HCH₃ 2 3 tetrazole 83 NH H H OCH₃ H CH₃ 2 3 CONHSO₂CH₃ 84 NH H H OCH₃ HCH₃ 2 3 COOH 85 NH H OCH₃ F H CH₃ 1 none COOH 86 NH H Br H OCH₃ CH₃ 1none COOH 87 NH H CH₃ H OCH₃ CH₃ none COOH 88 NH CH₃ H F H CH₃ none COOH89 NH H H H CH₃ CH₃ 1 none C(O)N(Na⁺) SO₂CH₃ 90 NH H H H Ethyl CH₃ 1none COOH 91 NH H H H CH₃ CH₃ 1 3 COOH 92 NH H H H CH₃ H 1 none COOH 93NH H H H CH₃ H 2 none COOH 94 NH H H H Isopropyl CH₃ 1 none COOH 95 NHCH₃ H H CH₃ CH₃ 1 none COOH 96 NH CH₃ H H CH₃ CH₃ 1 3 COOH 97 NH CH₃ H HCH₃ H 1 none COOH 98 NH OCH₃ H H CH₃ CH₃ 1 none COOH 99 NH OCH₃ H H CH₃CH₃ 1 3 COOH 100 NH H H H CH₃ H 1 none COOH 101 NH F H H CH₃ CH₃ 1 noneCOOH 102 NH F H H CH₃ CH₃ 1 3 COOH 103 NH F H H CH₃ H 1 none COOH 104 NHH CH₃ H CH₃ CH₃ 1 3 COOH 105 NH H CH₃ H CH₃ H 1 none COOH 106 O H H HCH₃ CH₃ 1 none COOH **Size Ring is the size of the ring formed when R₉and R₁₀ together with the carbon to which they are attached areconnected to form a spiro ring of the size 3, 4, 5, 6, or 7. Forexample, when the size of the ring is 3, the ring is cyclopropyl.

A representative compound is Compound 46:

In general, in another aspect, the present invention relates to the useof olanzapine analogs of Formulae I-IVe to modulate sleep. Typically,compounds of Formulae I-IVe modulate sleep with decreased side effects:e.g., the compounds do not inhibit REM sleep (consequently, sleepinduced by these compounds may more closely resemble a person's naturalsleep cycles), use of the compounds does not result in rebound insomnia,and/or the compounds do not inhibit locomotor activity or adverselyeffect body temperature.

In vitro selection criteria for olanzapine analogs of the invention areshown in Table 2.

TABLE 2 In Vitro Binding Criteria H1 Binding (Primary Target) Ki <500nMolar Off Target Binding Cholinergic M1, M2, M3 Ki >10 times themeasured H1 receptor Ki and/or >1,000 nm Dopamine D1, D2 Ki >10 timesthe measured H1 receptor Ki and/or >1,000 nm Adrenergic α1, α2 Ki >10times the measured H1 receptor Ki and/or >1,000 nm

For example, the off target binding Ki is 50 times the measured H1receptor Ki. In some embodiments, the off target binding Ki is 100 timesthe measured H1 receptor Ki.

In vitro binding assays are used to determine H1 binding (i.e., primarytarget binding) and M1, M2 and M3 binding (i.e., off target binding).These binding assays measure the ability of olanzapine analogs todisplace known standards from the H1, M1, M2, and M3 receptors, whereinH1 is a histamine receptor, and M1, M2, and M3 are cholinergic(muscarinic) receptors. Similar assays are performed with H1 anddopamine receptors (D1, and D2), and with H1 and adrenergic receptors(α1 and α2).

The binding studies against the histamine receptor, H1, indicate bindingaffinity, and therefore, the results of the binding assays are anindication of the activity of the olanzapine analog compound. Thebinding studies against the muscarinic receptors indicate the extent towhich the compounds bind the muscarinic receptors responsible foranti-cholinergic activity of the compound. Binding to muscarinicreceptors results in several undesired side effects of many knownantihistamines, e.g., dry-mouth. A decrease in the binding of thecompounds to the M1-M3 receptors, relative to the binding of thecompound to the H1 receptor, is an indication of the greater specificityof the compound for the histamine receptor over the muscarinic receptor.Moreover, a drug with increased specificity for the histamine receptorpossesses less anti-cholinergic side effects.

The H1 binding of olanzapine analogs of the invention (also referred toherein as “test compounds” or “compounds of the invention”) isdetermined by measuring the specific binding of a given test compound,or series of test compounds, to the H1 receptor, and comparing it withthe specific binding of known standard (i.e., reference compound).Reference compounds used in this H1 binding assay include, for example,triprolidine (K_(i) 3.3 nM), chlorpheniramine (K_(i) 103.0 nM),pyrilamine (K_(i) 1.9 nM), cyproheptadine (K_(i) 8.5 nM), cimetidine(K_(i)>10,000) and dimaprit (K_(i)>10,000). (See e.g., Chang et al., J.Neurochem., 32:1653-63 (1979) (with modifications); Martinez-Mir, etal., Brain Res., 526:322-27 (1990); and Haaksme, et al., Pharmac. Ther.,47:73-104 (1990).

For example, in one embodiment of the H1 binding assay, the H1 receptoris from bovine cellular membranes, and a radioligand, [³H]Pyrilamine(15-25 Ci/mmol) at a final ligand concentration of 2.0 nM is used todetect specific binding for the H1 receptor. The assay characteristicsinclude a K_(D) (binding affinity) of 1.3 nM and a B_(max) (receptornumber) of 6.2 fmol/mg tissue (wet weight). Tripolidine (10 μM) is usedas the non-specific determinant, reference compound and positivecontrol. Binding reactions are carried out in 50 mM NA-KPO₄ (pH 7.5) at25° C. for 60 minutes. The reaction is terminated by rapid vacuumfiltration onto glass fiber filters. The level of radioactivity trappedon the filters is measured and compared to control values to ascertainany interaction between a given test compound and the H1 binding site.

The M1 binding assay determines the M1 binding of a test compound bymeasuring the specific binding of a given test compound to M1 andcomparing it with the specific binding of a reference compound. (Seee.g., Buckley, et al., Mol. Pharmacol. 35:469-76 (1989) (withmodifications)). Reference compounds used in the M1 binding assayinclude, for example, scopolamine, MethylBr (K_(i) 0.09 nM); 4-DAMPmethiodide (K_(i) 0.27 nM); pirenzepine (K_(i) 2.60 nM); HHSID (K_(i)5.00 nM); and methoctramine (K_(i) 29.70 nM).

For example, in one embodiment of the M1 binding assay, the M1muscarinic receptor is a human recombinant M1 expressed in CHO cells,and a radioligand, [³H]-scopolamine, N-methyl chloride (80-100 Ci/mmol)at a final ligand concentration of 0.5 nM is used to detect specificbinding for M1. The assay characteristics include a K_(D) (bindingaffinity) of 0.05 nM and a B_(max) (receptor number) of 4.2 pmol/mgprotein. (−)-scopolamine, methyl-, bromide (methylscopolamine bromide)(1.0 μM) is used as the non-specific determinant, reference compound andpositive control. Binding reactions are carried out in PBS for 60minutes at 25° C. The reaction is terminated by rapid vacuum filtrationonto glass fiber filters. The level of radioactivity trapped on thefilters is measured and compared to control values to ascertain anyinteraction between a given test compound and the cloned muscarinic M1binding site.

The M2 binding assay determines the M2 binding of a test compound bymeasuring the specific binding of a given test compound to M2 andcomparing it with the specific binding of a reference compound. (Seee.g., Buckley, et al., Mol. Pharmacol. 35:469-76 (1989) (withmodifications)). Reference compounds used in the M2 binding assayinclude, for example, scopolamine, MethylBr (K_(i) 0.3 nM); 4-DAMPmethiodide (K_(i) 20.7 nM); methoctramine (K_(i) 20.460 nM); HHSID(K_(i) 212.7 nM); and pirenzepine (K_(i) 832.9 nM).

For example, in one embodiment of the M2 binding assay, the M2muscarinic receptor is a human recombinant M2 expressed in CHO cells,and a radioligand, [³H]-scopolamine, N-methyl chloride (80-100 Ci/mmol)at a final ligand concentration of 0.5 nM is used to detect specificbinding for M1. The assay characteristics include a K_(D) (bindingaffinity) of 0.29 nM and a B_(max) (receptor number) of 2.1 pmol/mgprotein. (−)-scopolamine, methyl-, bromide (methylscopolamine bromide)(1.0 μM) is used as the non-specific determinant, reference compound andpositive control. Binding reactions are carried out in PBS for 60minutes at 25° C. The reaction is terminated by rapid vacuum filtrationonto glass fiber filters. The level of radioactivity trapped on thefilters is measured and compared to control values to ascertain anyinteraction between a given test compound and the cloned muscarinic M2binding site.

The M3 binding assay determines the M3 binding of a test compound bymeasuring the specific binding of a given test compound to M3 andcomparing it with the specific binding of a reference compound. (Seee.g., Buckley, et al., Mol. Pharmacol. 35:469-76 (1989) (withmodifications)). Reference compounds used in the M3 binding assayinclude, for example, scopolamine, MethylBr (K_(i) 0.3 nM); 4-DAMPmethiodide (K_(i) 0.8 nM); HHSID (K_(i) 14.5 nM); pirenzepine (K_(i)153.3 nM); and methoctramine (K_(i) 700.0 nM).

For example, in one embodiment of the M3 binding assay, the M3muscarinic receptor is a human recombinant M3 expressed in CHO cells,and a radioligand, [³H]-scopolamine, N-methyl chloride (80-100 Ci/mmol)at a final ligand concentration of 0.2 nM is used to detect specificbinding for M1. The assay characteristics include a K_(D) (bindingaffinity) of 0.14 nM and a B_(max) (receptor number) of 4.0 pmol/mgprotein. (−)-scopolamine, methyl-, bromide (methylscopolamine bromide)(1.0 μM) is used as the non-specific determinant, reference compound andpositive control. Binding reactions are carried out in 50 mM TRIS-HCl(pH 7.4) containing 10 mM MgCl₂, 1 mM EDTA for 60 minutes at 25° C. Thereaction is terminated by rapid vacuum filtration onto glass fiberfilters. The level of radioactivity trapped on the filters is measuredand compared to control values to ascertain any interaction between agiven test compound and the cloned muscarinic M3 binding site.

In vitro selection criteria for olanzapine analogs of the invention areshown in Table 3.

TABLE 3 In Vitro Binding Criteria H1 Binding (Primary Target) Ki <300nMolar Off Target Binding Cholinergic M1 Ki >1 uM Cholinergic M2 Ki >1uM Cholinergic M3 Ki >1 uM

For example, other in vitro selection criteria for olanzapine analogs ofthe invention are shown in Table 4.

TABLE 4 In Vitro Binding Criteria H1 Binding (Primary Target) Ki <150nMolar Off Target Binding Cholinergic M1 Ki >10 uM Cholinergic M2 Ki >10uM Cholinergic M3 Ki >10 uM

H1 binding and M1, M2 and M3 binding (off target binding) are determinedusing the H1, M1, M2 and M3 binding assays described above.

Other in vitro selection criteria for olanzapine analogs of theinvention includes HERG binding. Primary target binding and off targetbinding are determined as described above. If the test compound exhibitsthe desired primary target (H1) binding and primary target/off targetbinding ration, HERG binding (off target binding) is determined using ahERG block comparative study to evaluate the effect of a given testcompound on cloned hERG channels expressed in mammalian cells. (Seee.g., Brown and Rampe, Pharmaceutical News 7:15-20 (2000); Rampe et al.,FEBS Lett., 417:28-32 (1997); Weirich and Antoni, Basic Res. Cardiol. 93Suppl. 1:125-32 (1998); and Yap and Camm, Clin. Exp. Allergy, 29 Suppl3, 174-81 (1999)).

Off target binding of hERG, the cardiac potassium channel responsiblefor the rapid delayed rectifier current (I_(Kr)) in human ventricles, isevaluated because inhibition of I_(Kr) is the most common cause ofcardiac action potential prolongation by non-cardiac drugs. (See Brownand Rampe (2000), Weirich and Antoni (1998); and Yap and Camm (1999)).Increased action potential duration causes prolongation of the QTinterval that has been associated with a dangerous ventriculararrhythmia, torsade de pointes. (Brown and Rampe (2000)).

In the hERG assay, hERG channels are expressed in a human embryonickidney cell line (HEK293) that lacks endogenous I_(Kr). Expression in amammalian cell line is preferable to transient expression in Xenopusoocytes, as the latter demonstrates a consistent 10-100 fold lowersensitivity to hERG channel blockers. (See, Rampe 1997).

In one embodiment of the hERG assay, the positive control (i.e.,reference compound) is terfenadine (Sigma, St. Louis Mo.), which hasbeen shown, at a concentration of 60 nM, to block hERG current byapproximately 75%. Test compounds are delivered in HEPES-bufferedphysiological saline (HB-PS)+0.1% dimethyl sulfoxide (DMSO). Each testcompound is applied at a concentration of 10 μM to the HEK293 cellsexpressing hERG (n≧3, where n=the number of cells). Cells are exposed tothe test compound for the time necessary to reach steady-state block,but not longer than 10 minutes. The positive control (60 mM terfenadine)is applied to two cells (n≧2).

The hERG-exposed cells are then transferred to the recording chamber andsuperfused with HB-PS solution. The pipette solution for whole cellrecordings includes potassium aspartate (130 mM), MgCl₂ (5 mM), EGTA (5mM), ATP (4 mM), and HEPES (10 mM) at a pH adjusted to 7.2 with KOH.Onset and steady state block of hERG current due to the test compoundare measured using a pulse pattern with fixed amplitudes(depolarization: +20 mV for 2 seconds; repolarization: −50 mV for 2seconds), repeated at 10 second intervals, from a holding potential of−80 mV. Peak tail current is measured during the 2 second step to −50mV. A steady state is maintained for at least 30 seconds before applyingthe test compound or positive control compound. Peak tail currents aremeasured until a new steady state is achieved.

In addition to the in vitro selection criteria described above,olanzapine analogs of the invention are selected using the following invivo sleep-wake and physiological assessments:

NonREM Sleep: Olanzapine analogs are selected if, in adult, male Wistarrats, (i) peak nonREM amount exceeds 55% nonREM per hour by no laterthan the third hour post-treatment; and (ii) the nature of this increasein nonREM sleep is such that the net cumulative total increase in nonREMsleep in the initial 6 hours post-treatment (adjusted for baseline atthe corresponding circadian time 24 hours earlier, and relative toVehicle control treatment) is not less than 20 minutes in total forcompound doses that produces maximum sleep consolidation as measured bysleep bout length, when drug is delivered orally.

The term “nonREM peak sleep time” is defined as an absolute peak amountof nonREM sleep per hour post treatment, with drug administrationoccurring at Circadian Time (CT) 18, which is 6 hours after lights offin a nocturnal laboratory rat when housed in a LD 12:12 (12-hours lightand 12 hours dark) light-dark cycle. The nominal criteria of 55% nonREMsleep per hour is equivalent to 33 minutes of nonREM sleep per hour.

As used herein, the term “cumulative nonREM sleep” is defined as the nettotal aggregate increase in the number of minutes of nonREM sleep,measured through out the entire duration of a drug's soporific effect,which typically, but not always occurs in the first 6 hourspost-treatment, adjusted for the net total aggregate number of minutesof nonREM sleep that occurred during the corresponding non-treatmentbaseline times of day recorded 24 hours earlier, relative to likevehicle control treatment.

As defined herein, the term “sleep bout” refers to a discrete episode ofcontinuous or near continuous sleep, comprised of nonREM sleep, REMsleep, or both nonREM and REM sleep stages, delimited prior and afterthe episode by greater than two contiguous 10 second epochs ofwakefulness. The following non-limiting description illustrates thisconcept: WWWWSSSSWSSSSSSSWWSSSSSSSWWWW, wherein each letter representsthe predominant state of arousal (S=sleep, W=wake) observed each 10seconds. The measured sleep “bout” is 21 ten-second epochs or 3.5minutes in duration.

Sleep Consolidation: Olanzapine analogs are selected if, in adult maleWistar rats, (i) the absolute duration of longest continuous sleepepisodes (i.e., “sleep bout”) post-treatment is greater than 13 minutesin duration; (ii) the net longest sleep bout post treatment is greaterthan or equal to 3 minutes when adjusted for baseline 24 hours earlierand calculated relative to vehicle treatment; and (iii) the meanabsolute duration of every sleep bout when averaged per hour, on an hourby hour basis, is greater than or equal to 5 minutes. The aforementionedselection criteria assume that stages of sleep and wakefulness aredetermined continuously every 10 seconds (e.g., 10 second sleep scoring“epochs”), that sleep and wakefulness are measured polygraphically usingEEG and EMG criteria, and sleep episodes (comprised of nonREM and/or REMsleep) are defined as continuous “bouts” until the episode isinterrupted by greater than two contiguous 10 second epochs ofwakefulness.

As used herein, the term “longest sleep bout length” is defined as thetotal number of minutes an animal remains asleep (nonREM and/or REMsleep stages) during the single longest sleep bout that occurredbeginning in a given hour post-treatment. The “sleep bout length”measurement criteria assumes sleep is measured continuously in 10 secondepochs, and is scored based upon the predominant state, computed orotherwise determined as a discrete sleep stage (where sleep stages aredefined as nonREM sleep, REM sleep, or wakefulness) during the 10 secondinterval that defines the epoch.

The term “average sleep bout length” is defined as the average duration(in minutes) of every and all sleep episodes or bouts that began in agiven hour, independent of the individual duration of each episode orbout.

Concurrently Measured Side Effects: Olanzapine analogs are selected if,in adult, male Wistar rats, these compounds (i) do not produceappreciable amounts of rebound insomnia; (ii) do not appreciably inhibitREM sleep; and (iii) do not disproportionately inhibit locomotor motoractivity and/or motor tone relative to the normal effects of sleepitself. The threshold definitions for these three side-effect variablesare as follows:

“Rebound insomnia” is defined as period of rebound, paradoxical, orcompensatory wakefulness that occurs after the sleep promoting effectsof a hypnotic or soporific agent. Rebound insomnia is typically observedduring the usual circadian rest phase 6-18 hours post-treatment at CT-18(6 hours after lights-off, given LD 12:12), but can occur at any timeduring the initial 30 hours post-treatment. Rebound is consideredunacceptable when, in the adult, male Wistar rat, excess cumulativewakefulness associated with rebound insomnia is greater than 10%reduction in average of hourly NonREM sleep times during post-treatmentcircadian rest phase (lights-on).

In adult, male Wistar rats, rebound insomnia manifests as an increase inwakefulness relative to corresponding times at baseline (24 hoursearlier) subsequent to a drug-induced sleep effect, and rebound insomniais measured cumulatively.

“REM sleep inhibition” is defined as the reduction of REM sleep timepost-treatment at CT-18 (6 hours after lights-off; LD 12:12) or at CT-5(5 hours after lights-on; LD 12:12). Compounds that reduce REM sleeptime by greater than 15 minutes (relative to baseline and adjusted forvehicle treatment) when administered at either CT-18 or CT-5 areconsidered unacceptable.

As defined herein, “disproportionate locomotor activity inhibition” is areduction of locomotor activity that exceeds the normal and expectedreduction in behavioral activity attributable to sleep. Logic dictatesthat if an animal is asleep, there will normally be a correspondingreduction in locomotor activity. If a hypnotic or soporific compoundreduces locomotor activity levels in excess of 20% greater than thatexplained by sleep alone, the compound is deemed unacceptable. Locomotoractivity (LMA) or motor tone may be quantified objectively using anyform of behavioral locomotor activity monitor (non-specific movements,telemetry-based activity monitoring, 3-dimensional movement detectiondevices, wheel running activity, exploratory measures, electromyographicrecording, etc.) so long as it is measured concurrently with objectivesleep-wakefulness measures in the same animal.

In one embodiment, locomotor activity within the animal's cage ismeasured using a biotelemetry device surgically implanted in theanimal's peritoneal cavity; the implantable device and associatedtelemetry receiver detects if and how much animal moves within the cage.Sleep and wakefulness is measured in 10 second epochs simultaneously.Counts of locomotor activity per unit time are divided by the concurrentamount of wakefulness per the same unit, yielding a “locomotor activityintensity” (LMAI) measure for that unit time. Hypnotic or soporificcompounds administered at CT-18 (6 hours after lights-off; LD 12:12)that decrease locomotor activity per unit time awake by greater than 20%relative to vehicle would be judged unacceptable.

In an embodiment, the olanzapine analogs of the invention are selectedusing the in vivo sleep-wake and physiological assessment criteria shownin Table 5:

TABLE 5 Change from baseline value relative to vehicle SCORE-2000Absolute Value only NonREM Peak Time >55% sleep/hour peak Not applicableCumulative NonREM Not applicable >20 minutes at ED100 for MSBL at T₁₋₆Longest Sleep Bout >17 minutes absolute peak >5 minutes Average SleepBout >6 minutes absolute peak Not used in SAR cuts Rebound Insomnia <10%reduction in average of Not applicable hourly NonREM sleep times duringpost-treatment circadian rest phase (lights-on) REM Sleep Inhibition notapplicable not to exceed 15 minutes, Rx at CT5 LMAI not applicable notto exceed 20% LMAI reduction

Methods for evaluating these sleep-wake and physiological assessmentcriteria are described above. The “absolute value” shown in secondcolumn of Table 5 refers to the value as determined for each testcompound, while the “change” value shown in the third column of Table 5reflects an adjusted value in which the absolute value is the differencefrom vehicle, when the vehicle values are adjusted for baseline.

In some embodiments, the longest sleep bout is greater than 13 minutesin duration. In others, it is greater than 17 minutes in duration. Insome embodiments, the net longest sleep bout post treatment is greaterthan or equal to 3 minutes in duration. In others, it is greater than orequal to 6 minutes in duration.

Other in vivo sleep-wake and physiological assessment criteria used toselect olanzapine analogs of the invention include measurement of acutebody temperature and latent body temperature as a change in baselinerelative to vehicle. The acute body temperature change should not exceed−0.50° C., and the latent body temperature change should not exceed+0.50° C. at Time 1-6 hours. The acute body temperature (T₁₋₆) isadjusted for the corresponding baseline measured 24 hours earlier,relative to vehicle (the decrease from vehicle). The latent bodytemperature, measured 7-18 hours post drug treatment (T₇₋₁₈), isadjusted for the corresponding baseline measured 24 hours earlier,relative to vehicle (the decrease from vehicle).

The invention provides a method of modulating sleep by administering toa subject a therapeutically effective amount of a compound of FormulaI-IVe or a pharmaceutically effective salt thereof. The compoundsmodulate sleep in several ways, including decreasing the time to sleeponset, increasing the average sleep bout length, and increasing themaximum sleep bout length.

The compounds, or pharmaceutically acceptable salts thereof, isadministered orally, nasally, transdermally, pulmonary, inhalationally,buccally, sublingually, intraperintoneally, intravenously, rectally,intrapleurally, intrathecally and parenterally. In one embodiment, thecompound is administered orally. One skilled in the art will recognizethe advantages of certain routes of administration.

The method of modulating sleep by administering to a subject atherapeutically effective amount of a compound of Formula I-IVe or apharmaceutically effective salt thereof is used to treat a variety ofsleep disorders including circadian rhythm abnormality, insomnia,parasomnia, sleep apnea syndrome, narcolepsy and hypersomnia. In oneembodiment, the method treats circadian rhythm abnormalities includingjet lag, shift-work disorders, delayed sleep phase syndrome, advancedsleep phase syndrome and non-24 hour sleep-wake disorder. In anotherembodiment, the method treats insomnia including extrinsic insomnia,psychophysiologic insomnia, altitude insomnia, restless leg syndrome,periodic limb movement disorder, medication-dependent insomnia,drug-dependent insomnia, alcohol-dependent insomnia and insomniaassociated with mental disorders.

In another embodiment, the method treats parasomnias includingsomnambulism, pavor nocturnus, REM sleep behavior disorder, sleepbruxism and sleep enuresis. In yet another embodiment, the method treatssleep apnea disorder including central sleep apnea, obstructive sleepapnea and mixed sleep apnea. Additionally, the method treats other sleepdisorders such as narcolepsy or hypersomnia.

In some embodiments, a compound of Formula I-IVe is administered as apharmaceutically acceptable salt. For example, compound 89 is apharmaceutically acceptable sodium salt of compound 89a as shown below.

One skilled in the art will recognize the various methods for creatingpharmaceutically acceptable salts and identifying the appropriate salt.In one embodiment, the compound or a pharmaceutically acceptable saltthereof is included in a pharmaceutical composition.

A “subject” includes mammals, e.g., humans, companion animals (e.g.,dogs, cats, birds, and the like), farm animals (e.g., cows, sheep, pigs,horses, fowl, and the like) and laboratory animals (e.g., rats, mice,guinea pigs, birds, and the like). Typically, the subject is human.

A subject in need of treatment has a sleep disorder that can affect thesubject's ability to fall asleep and/or remain asleep, and/or results inunrefreshing sleep or non-restorative sleep.

As used herein, the term “sleep disorder” includes conditions recognizedby one skilled in the art as sleep disorders, for example, conditionsknown in the art or conditions that are proposed to be sleep disordersor discovered to be sleep disorders. See, for example, Thorpy, M JInternational Classification of Sleep Disorders, Revised: Diagnostic andCoding Manual. American Sleep Disorders Association; Rochester, Minn.1997; and ICD-9-CM, International Classification of Diseases, NinthRevision, Clinical Modification, National Center for Health Statistics,Hyattsville, Md.

For example, sleep disorders can be generally classed into dyssomnias,e.g., intrinsic, extrinsic, and circadian rhythm disorders; parasomnias,e.g., arousal, sleep-wake transition, and rapid eye movement (REM)associated disorders, and other parasomnias; disorders associated withmental, neurological, and other medical disorders; and other sleepdisorders.

Intrinsic sleep disorders include, for example, psychophysiologicalinsomnia, sleep state misperception, idiopathic insomnia, narcolepsy,recurrent hypersomnia, idiopathic hypersomnia, post-traumatichypersomnia, obstructive sleep apnea syndrome, central sleep apneasyndrome, central alveolar hypoventilation syndrome, periodic limbmovement disorder, and restless legs syndrome.

Extrinsic sleep disorders include, for example, inadequate sleephygiene, environmental sleep disorder, altitude insomnia, adjustmentsleep disorder, insufficient sleep syndrome, limit-setting sleepdisorder, sleep-onset association disorder, food allergy insomnia,nocturnal eating (drinking) syndrome, hypnotic-dependent sleep disorder,stimulant-dependent sleep disorder, alcohol-dependent sleep disorder,and toxin-induced sleep disorder.

Circadian rhythm sleep disorders include, for example, time-zone change(jet lag) syndrome, shift work sleep disorder, irregular sleep-wakepattern, delayed sleep phase syndrome, advanced sleep phase syndrome,and non-24-hour sleep-wake disorder.

Arousal sleep disorders include, for example, confusional arousals,sleepwalking and sleep terrors.

Sleep-wake transition disorders include, for example, rhythmic movementdisorder, sleep starts, sleeptalking, and nocturnal leg cramps.

REM-associated sleep disorders include, for example, nightmares, sleepparalysis, impaired sleep-related penile erections, sleep-relatedpainful erections, REM sleep-related sinus arrest, and REM sleepbehavior disorder.

Other parasomnias include, for example, sleep bruxism, sleep enuresis,sleep-related abnormal swallowing syndrome, nocturnal paroxysmaldystonia, sudden unexplained nocturnal death syndrome, primary snoring,infant sleep apnea, congenital central hypoventilation syndrome, suddeninfant death syndrome, and benign neonatal sleep myoclonus.

A “sleep disorder” also arises in a subject that has other medicaldisorders, diseases, or injuries, or in a subject being treated withother medications or medical treatments, where the subject as a resulthas difficulty falling asleep and/or remaining asleep, or experiencesunrefreshing sleep or non-restorative sleep, e.g., the subjectexperiences sleep deprivation. For example, some subjects havedifficulty sleeping after undergoing medical treatment for otherconditions, e.g., chemotherapy or surgery, or as a result of pain orother effects of physical injuries.

It is well known in the art that certain medical disorders, for example,central nervous system (CNS) disorders, e.g. mental or neurologicaldisorders, e.g., anxiety, can have a sleep disorder component, e.g.,sleep deprivation. Thus, “treating a sleep disorder” also includestreating a sleep disorder component of other disorders, e.g., CNSdisorders. Further, treating the sleep disorder component of CNSdisorders can also have the beneficial effect of ameliorating othersymptoms associated with the disorder. For example, in some subjectsexperiencing anxiety coupled with sleep deprivation, treating the sleepdeprivation component also treats the anxiety component. Thus, thepresent invention also includes a method of treating such medicaldisorders.

For example, sleep disorders associated with mental disorders includepsychoses, mood disorders, anxiety disorders, panic disorder,addictions, and the like. Specific mental disorders include, forexample, depression, obsessive compulsive disorder, affectiveneurosis/disorder, depressive neurosis/disorder, anxiety neurosis;dysthymic disorder, behavior disorder, mood disorder, schizophrenia,manic depression, delirium, and alcoholism.

Sleep disorders associated with neurological disorders include, forexample, cerebral degenerative disorders, dementia, parkinsonism,Huntington's disease, Alzheimer's, fatal familial insomnia, sleeprelated epilepsy, electrical status epilepticus of sleep, andsleep-related headaches. Sleep disorders associated with other medicaldisorders include, for example, sleeping sickness, nocturnal cardiacischemia, chronic obstructive pulmonary disease, sleep-related asthma,sleep-related gastroesophageal reflux, peptic ulcer disease, andfibrositis syndrome.

In some circumstances, sleep disorders are also associated with pain,e.g., neuropathic pain associated with restless leg syndrome; migraine;hyperalgesia, fibromyalgia, pain; enhanced or exaggerated sensitivity topain, such as hyperalgesia, causalgia and allodynia; acute pain; burnpain; atypical facial pain; neuropathic pain; back pain; complexregional pain syndromes I and II; arthritic pain; sports injury pain;pain related to infection, e.g., HIV, post-polio syndrome, andpost-herpetic neuralgia; phantom limb pain; labor pain; cancer pain;post-chemotherapy pain; post-stroke pain; post-operative pain;neuralgia; conditions associated with visceral pain including irritablebowel syndrome, migraine and angina.

Other sleep disorders include, for example, short sleeper, long sleeper,subwakefulness syndrome, fragmentary myoclonus, sleep hyperhidrosis,menstrual-associated sleep disorder, pregnancy-associated sleepdisorder, terrifying hypnagogic hallucinations, sleep-related neurogenictachypnea, sleep-related laryngospasm, and sleep choking syndrome.

Insomnia is typically classed into sleep onset insomnia, where a subjecttakes more than 30 minutes to fall asleep; and sleep maintenanceinsomnia, where the subject spends more than 30 minutes awake during anexpected sleep period, or, for example, waking before the desiredwake-up time with difficulty or an inability to get back to sleep. Thedisclosed compounds are particularly effective in treating sleep onsetand sleep maintenance insomnias, insomnia resulting from circadianrhythm adjustment disorders, or insomnia resulting from CNS disorders.One embodiment is treating a subject for a circadian rhythm adjustmentdisorder. Another embodiment is treating a subject for insomniaresulting from a mood disorder. In other embodiments, a subject istreated for sleep apnea, somnambulism, night terrors, restless legsyndrome, sleep onset insomnia, or sleep maintenance insomnia.Typically, a patient is treated for sleep onset insomnia or sleepmaintenance insomnia. The disclosed compounds may be effective fortreating sleep onset insomnia. The disclosed compounds may also beeffective for treating sleep maintenance insomnia.

The dosage regimen utilizing the compounds is selected in accordancewith a variety of factors including type, species, age, weight, sex andmedical condition of the patient; the severity of the condition to betreated; the route of administration; the renal and hepatic function ofthe patient; and the particular compound or salt thereof employed. Anordinarily skilled physician or veterinarian can readily determine andprescribe the effective amount of the drug required to prevent, counteror arrest the progress of the condition.

Oral dosages of the present invention, when used for the indicatedeffects, will range between about 0.05 to 5000 mg/day orally. Effectiveamounts of the disclosed compounds typically range between about 0.01mg/kg per day and about 100 mg/kg per day, and typically between 0.1mg/kg per day and about 10 mg/kg/day. Techniques for administration ofthe disclosed compounds of the invention can be found in Remington: theScience and Practice of Pharmacy, 19^(th) edition, Mack Publishing Co.,Easton, Pa. (1995).

For example, in some embodiments, an acid salt of a compound containingan amine or other basic group is obtained by reacting the compound witha suitable organic or inorganic acid, such as hydrogen chloride,hydrogen bromide, acetic acid, perchloric acid and the like. Compoundswith a quaternary ammonium group also contain a counter anion such aschloride, bromide, iodide, acetate, perchlorate and the like. Otherexamples of such salts include hydrochlorides, hydrobromides, sulfates,methanesulfonates, nitrates, maleates, acetates, citrates, fumarates,tartrates (e.g. (+)-tartrates, (−)-tartrates or mixtures thereofincluding racemic mixtures), succinates, benzoates and salts with aminoacids such as glutamic acid.

Salts of compounds containing a carboxylic acid or other acidicfunctional group are prepared by reacting with a suitable base. Such apharmaceutically acceptable salt is made with a base which affords apharmaceutically acceptable cation, which includes alkali metal salts(especially sodium and potassium), alkaline earth metal salts(especially calcium and magnesium), aluminum salts and ammonium salts,as well as salts made from physiologically acceptable organic bases suchas trimethylamine, triethylamine, morpholine, pyridine, piperidine,picoline, dicyclohexylamine, N,N′-dibenzylethylenediamine,2-hydroxyethylamine, bis-(2-hydroxyethyl)amine,tri-(2-hydroxyethyl)amine, procaine, dibenzylpiperidine,N-benzyl-β-phenethylamine, dehydroabietylamine,N,N′-bisdehydroabietylamine, glucamine, N-methylglucamine, collidine,quinine, quinoline, and basic amino acid such as lysine and arginine.

In some embodiments, certain compounds and their salts also exist in theform of solvates, for example hydrates, and the present inventionincludes each solvate and mixtures thereof.

The disclosed compounds, and salts or solvates thereof may exist in morethan one crystal form, e.g., as “crystal polymorphs” or “polymorphs”.Crystal polymorphs of the disclosed compounds are prepared bycrystallization under different conditions. For example, using differentsolvents or different solvent mixtures for recrystallization;crystallization at different temperatures; various modes of cooling,ranging from very fast to very slow cooling during crystallization, andthe like. Polymorphs are also obtained by heating or melting thedisclosed compounds followed by gradual or fast cooling. The presence ofpolymorphs is determined by solid probe nuclear magnetic resonancespectroscopy, infrared spectroscopy, differential scanning calorimetry,powder X-ray diffraction, and other techniques known to one skilled inthe art.

In an embodiment, the compounds described herein, and thepharmaceutically acceptable salts thereof are used in pharmaceuticalpreparations in combination with a pharmaceutically acceptable carrieror diluent. Suitable pharmaceutically acceptable carriers include inertsolid fillers or diluents and sterile aqueous or organic solutions. Thecompounds will be present in such pharmaceutical compositions in amountssufficient to provide the desired dosage amount in the range describedherein. Techniques for formulation and administration of the disclosedcompounds of the invention can be found in Remington: the Science andPractice of Pharmacy, above.

Typically, the compound is prepared for oral administration, wherein thedisclosed compounds or salts thereof are combined with a suitable solidor liquid carrier or diluent to form capsules, tablets, pills, powders,syrups, solutions, suspensions and the like.

The tablets, pills, capsules, and the like contain from about 1 to about99 weight percent of the active ingredient and a binder such as gumtragacanth, acacias, corn starch or gelatin; excipients such asdicalcium phosphate; a disintegrating agent such as corn starch, potatostarch or alginic acid; a lubricant such as magnesium stearate; and/or asweetening agent such as sucrose, lactose, saccharin, xylitol, and thelike. When a dosage unit form is a capsule, it often contains, inaddition to materials of the above type, a liquid carrier such as afatty oil.

In some embodiments, various other materials are present as coatings orto modify the physical form of the dosage unit. For instance, in someembodiments, tablets are coated with shellac, sugar or both. In someembodiments, a syrup or elixir contains, in addition to the activeingredient, sucrose as a sweetening agent, methyl and propylparabens aspreservatives, a dye and a flavoring such as cherry or orange flavor,and the like.

For some embodiments relating to parental administration, the disclosedcompounds, or salts, solvates, or polymorphs thereof, can be combinedwith sterile aqueous or organic media to form injectable solutions orsuspensions. Injectable compositions are typically aqueous isotonicsolutions or suspensions. The compositions may be sterilized and/orcontain adjuvants, such as preserving, stabilizing, wetting oremulsifying agents, solution promoters, salts for regulating the osmoticpressure and/or buffers. In addition, they may also contain othertherapeutically valuable substances. The compositions are preparedaccording to conventional mixing, granulating or coating methods,respectively, and contain about 0.1 to 75%, typically about 1 to 50%, ofthe active ingredient.

For example, injectable solutions are produced using solvents such assesame or peanut oil or aqueous propylene glycol, as well as aqueoussolutions of water-soluble pharmaceutically-acceptable salts of thecompounds. In some embodiments, dispersions are prepared in glycerol,liquid polyethylene glycols and mixtures thereof in oils. Under ordinaryconditions of storage and use, these preparations contain a preservativeto prevent the growth of microorganisms. The terms “parenteraladministration” and “administered parenterally” as used herein meansmodes of administration other than enteral and topical administration,usually by injection, and includes, without limitation, intravenous,intramuscular, intraarterial, intrathecal, intracapsular, intraorbital,intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous,subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal andintrasternal injection and infusion.

For rectal administration, suitable pharmaceutical compositions are, forexample, topical preparations, suppositories or enemas. Suppositoriesare advantageously prepared from fatty emulsions or suspensions. Thecompositions may be sterilized and/or contain adjuvants, such aspreserving, stabilizing, wetting or emulsifying agents, solutionpromoters, salts for regulating the osmotic pressure and/or buffers. Inaddition, they may also contain other therapeutically valuablesubstances. The compositions are prepared according to conventionalmixing, granulating or coating methods, respectively, and contain about0.1 to 75%, typically about 1 to 50%, of the active ingredient.

In some embodiments, the compounds are formulated to deliver the activeagent by pulmonary administration, e.g., administration of an aerosolformulation containing the active agent from, for example, a manual pumpspray, nebulizer or pressurized metered-dose inhaler. In someembodiments, suitable formulations of this type also include otheragents, such as antistatic agents, to maintain the disclosed compoundsas effective aerosols.

A drug delivery device for delivering aerosols comprises a suitableaerosol canister with a metering valve containing a pharmaceuticalaerosol formulation as described and an actuator housing adapted to holdthe canister and allow for drug delivery. The canister in the drugdelivery device has a headspace representing greater than about 15% ofthe total volume of the canister. Often, the polymer intended forpulmonary administration is dissolved, suspended or emulsified in amixture of a solvent, surfactant and propellant. The mixture ismaintained under pressure in a canister that has been sealed with ametering valve.

For nasal administration, either a solid or a liquid carrier can beused. The solid carrier includes a coarse powder having particle size inthe range of, for example, from about 20 to about 500 microns and suchformulation is administered by rapid inhalation through the nasalpassages. In some embodiments where the liquid carrier is used, theformulation is administered as a nasal spray or drops and includes oilor aqueous solutions of the active ingredients.

Also contemplated are formulations that are rapidly dispersing dosageforms, also known as “flash dose” forms. In particular, some embodimentsof the present invention are formulated as compositions that releasetheir active ingredients within a short period of time, e.g., typicallyless than about five minutes, such as less than about ninety seconds,for example, in less than about thirty seconds or in less than about tenor fifteen seconds. Such formulations are suitable for administration toa subject via a variety of routes, for example by insertion into a bodycavity or application to a moist body surface or open wound.

Typically, a “flash dosage” is a solid dosage form that is administeredorally, which rapidly disperses in the mouth, and hence does not requiregreat effort in swallowing and allows the compound to be rapidlyingested or absorbed through the oral mucosal membranes. In someembodiments, suitable rapidly dispersing dosage forms are also used inother applications, including the treatment of wounds and other bodilyinsults and diseased states in which release of the medicament byexternally supplied moisture is not possible.

“Flash dose” forms are known in the art; see for example, effervescentdosage forms and quick release coatings of insoluble microparticles inU.S. Pat. Nos. 5,578,322 and 5,607,697; freeze dried foams and liquidsin U.S. Pat. Nos. 4,642,903 and 5,631,023; melt spinning of dosage formsin U.S. Pat. Nos. 4,855,326, 5,380,473 and 5,518,730; solid, free-formfabrication in U.S. Pat. No. 6,471,992; saccharide-based carrier matrixand a liquid binder in U.S. Pat. Nos. 5,587,172, 5,616,344, 6,277,406,and 5,622,719; and other forms known to the art.

The olanzapine analogs of the invention are also formulated as “pulsedrelease” formulations, in which the analog is released from thepharmaceutical compositions in a series of releases (i.e., pulses). Theolanzapine analogs are also formulated as “sustained release”formulations in which the analog is continuously released from thepharmaceutical composition over a prolonged period.

Also contemplated are formulations, e.g., liquid formulations, includingcyclic or acyclic encapsulating or solvating agents, e.g.,cyclodextrins, polyethers, or polysaccharides (e.g., methylcellulose),or typically, polyanionic β-cyclodextrin derivatives with a sodiumsulfonate salt group separate from the lipophilic cavity by an alkylether spacer group or polysaccharides. In one embodiment, the agent ismethylcellulose. In another embodiment, the agent is a polyanionicβ-cyclodextrin derivative with a sodium sulfonate salt separated fromthe lipophilic cavity by a butyl ether spacer group, e.g., CAPTISOL®(CyDex, Overland, Kans.). One skilled in the art can evaluate suitableagent/disclosed compound formulation ratios by preparing a solution ofthe agent in water, e.g., a 40% by weight solution; preparing serialdilutions, e.g. to make solutions of 20%, 10, 5%, 2.5%, 0% (control),and the like; adding an excess (compared to the amount that can besolubilized by the agent) of the disclosed compound; mixing underappropriate conditions, e.g., heating, agitation, sonication, and thelike; centrifuging or filtering the resulting mixtures to obtain clearsolutions; and analyzing the solutions for concentration of thedisclosed compound.

In addition to the therapeutic formulations described above, a therapyincluding the compounds of the present invention optionally includes,co-administration with one or more additional therapies, e.g., drugs orphysical or behavioral treatments (e.g., light therapy, electricalstimulation, behavior modification, cognitive therapy, circadian rhythmmodification, and the like). Such a practice is referred to as“combination therapy.” The other therapy or therapies in the combinationtherapy include therapies recognized by one skilled in the art asdesirable in combination with the compound of the invention, forexample, therapies known to the art or therapies which are proposed ordiscovered in the art for treating sleep disorders or treating diseasesassociated with sleep disorders, for example, therapies for any of thesleep disorders or other conditions disclosed herein. In someembodiments the compound is administered as a combination therapywhereas it is administered as a monotherapy in other embodiments.

Typically, the compound is administered as a monotherapy.

One skilled in the art will appreciate that a therapy administered incombination with the compounds of the present invention is directed tothe same or a different disorder target as that being targeted by thecompounds of the present invention. Administration of the compound ofthe invention is first, followed by the other therapy; or alternatively,administration of the other therapy may be first. The other therapy isany known in the art to treat, prevent, or reduce the symptoms of thetargeted disorder, e.g., a sleep disorder, or other disorders, e.g.,other CNS disorders. In addition, some embodiments of the presentinvention have compounds administered in combination with other knowntherapies for the target disorder. Furthermore, the other therapyincludes any agent of benefit to the patient when administered incombination with the disclosed compound.

For example, in some embodiments where the other therapy is a drug, itis administered as a separate formulation or in the same formulation asthe compound of the invention. A compound of the invention isadministered in combination therapy with any one or more ofcommercially-available, over-the-counter or prescription medications,including, but not limited to antihistamines, antimicrobial agents,fungistatic agents, germicidal agents, hormones, antipyretic agents,antidiabetic agents, bronchodilators, antidiarrheal agents,antiarrhythmic agents, coronary dilation agents, glycosides,spasmolytics, antihypertensive agents, antidepressants, antianxietyagents, other psychotherapeutic agents, steroids, corticosteroids,analgesics, cold medications, vitamins, sedatives, hypnotics,contraceptives, nonsteroidal anti-inflammatory drugs, blood glucoselowering agents, cholesterol lowering agents, anticonvulsant agents,other antiepileptic agents, immunomodulators, anticholinergics,sympatholytics, sympathomimetics, vasodilatory agents, anticoagulants,antiarrhythmics, prostaglandins having various pharmacologic activities,diuretics, sleep aids, antihistaminic agents, antineoplastic agents,oncolytic agents, antiandrogens, antimalarial agents, antileprosyagents, and various other types of drugs. See Goodman and Gilman's TheBasis of Therapeutics (Eighth Edition, Pergamon Press, Inc., USA, 1990)and The Merck Index (Eleventh Edition, Merck & Co., Inc., USA, 1989).

All publications and patent documents cited herein are incorporatedherein by reference as if each such publication or document wasspecifically and individually indicated to be incorporated herein byreference. Citation of publications and patent documents is not intendedas an admission that any is pertinent prior art, nor does it constituteany admission as to the contents or date of the same. The inventionhaving now been described by way of written description, those of skillin the art will recognize that the invention can be practiced in avariety of embodiments and that the foregoing description and examplesbelow are for purposes of illustration and not limitation of the claimsthat follow.

EXAMPLE 1 Synthesis of Olanzapine Analogs

The compounds of the invention, and related derivatives, can besynthesized by methods known to one skilled in the art.

EXAMPLE 2 Properties of Compounds of the Invention

Binding assays were performed using various sleep-inducing agents andderivatives selected from those listed in Table 1 in competitive bindingassays with known standards for the H1 histamine receptor, and the M1,M2, and M3 muscarinic receptors, alpha 1 and alpha 2 receptors, D1 andD2 receptors, 5HT2a, 5HT2b, 5HT2c, 5HT2c, and 5HT7 receptors.

The histamine H1 assays are described in Chang, et al., Heterogeneity ofHistamine H₁-Receptors: Species Variation in [³H]Mepyramine Binding ofBrain Membranes. Journal of Neurochemistry. 32: 1653-1663 (1979);Martinez-Mir, M. I., Pollard, H., Moreau, J., et al. Three HistamineReceptors (H₁, H₂, and H₃) Visualized in the Brain of Human andNon-Human Primates. Brain Res. 526: 322-327 (1990); Haaksma, E. E. J.,Leurs, R. and Timmerman, H. Histamine Receptors: Subclasses and SpecificLigands. Pharmac. Ther. 47: 73-104 (1990). The muscarinic assays aredescribed in Buckley, N. J., Bonner, T. I., Buckley, C. M., and Brann,M. R. Antagonist Binding Properties of Five Cloned Muscarinic ReceptorsExpressed in CHO-K1 Cells. Mol. Pharmacol. 35: 469-476 (1989). Theassays were performed according to the preceding articles, with thefollowing modifications. Chemical reagents in the following wereobtained from Sigma, St. Louis, Mo.

For the histamine H1 assays, the receptors were obtained from bovinecerebellar membrane tissue, with a B_(max) (receptor number) of 6.2femtomol/mg tissue (wet weight) and a KD (binding affinity) of 1.3 nM. Aradioactive ligand ([³H]pyrilamine (15-25)Ci/mmol), K_(i) 1.9 nM, finalconcentration 2.0 nM) was employed, and 10 μM triprolidine (K_(i) 3.3nM) was employed as a non-specific determinant, reference compound, andpositive control. The receptor and the radioactive ligand were combinedwith the test compound at a range of test compound concentrations fromabout 10⁻¹⁰ to about 10⁻⁶ M, and the mixture was incubated out in 50 mMNa—KPO₄ (pH 7.5) at 25° C. for 60 minutes. The reaction was terminatedby rapid vacuum filtration onto glass fiber filters. Radioactivity fromthe displaced radioactive ligand trapped onto the filters was determinedand compared to control values in order to measure any interactions ofthe test compound with the histamine H1 binding site.

For the muscarinic assays, the receptors were obtained from humanrecombinant receptors expressed in CHO cells (PerkinElmer, Inc.,Wellesley, Mass.). The radioactive ligand employed was [³H]-scopolamine,N-methyl chloride (80-100 Ci/mmol). (−)-Methylscopolamine bromide, 1.0μM, was employed as the non-specific determinant, reference compound,and positive control. After incubation, reactions were terminated byrapid vacuum filtration onto glass fiber filters. Radioactivity from thedisplaced radioactive ligand trapped onto the filters was determined andcompared to control values in order to measure any interactions of thetest compound with the respective receptor.

For the M1 receptor assay, the B_(max) (receptor number) was 4.2picomol/mg protein, and the K_(D) (binding affinity) of the receptor was0.05 nM. The radioactive ligand was employed at a final concentration0.5 nM, while the (−)-methylscopolamine bromide had a K_(i) of 0.09 nM.The receptor and the radioactive ligand were combined with the testcompound at a range of test compound concentrations from about 10⁻¹² toabout 10⁻⁵ M, incubated in Dulbecco's Phosphate Buffered Saline (PBS)for 60 minutes at 25° C., and worked up as described above.

For the M2 receptor assay, the B_(max) (receptor number) was 2.1picomol/mg protein, and the K_(D) (binding affinity) of the receptor was0.29 nM. The radioactive ligand was employed at a final concentration0.5 nM, while the (−)-methylscopolamine bromide had a K_(i) of 0.3 nM.The receptor and the radioactive ligand were combined with the testcompound at a range of test compound concentrations from about 10⁻¹² toabout 10⁻⁵ M, incubated in Dulbecco's Phosphate Buffered Saline (PBS)for 60 minutes at 25° C., and worked up as described above.

For the M3 receptor assay, the B_(max) (receptor number) was 4.0picomol/mg protein, and the K_(D) (binding affinity) of the receptor was0.14 nM. The radioactive ligand was employed at a final concentration0.2 nM, while the (−)-methylscopolamine bromide had a K_(i) of 0.3 nM.The receptor and the radioactive ligand were combined with the testcompound at a range of test compound concentrations from about 10⁻¹² toabout 10⁻⁵ M, incubated in 50 mM TRIS-HCl (pH 7.4) containing 10 mMMgCl₂, 1 mM EDTA for 60 minutes at 25° C., and worked up as describedabove.

Dopamine, D₁ (human recombinant) binding assay was performed accordingto published procedures. See, e.g., Jarvie, et al. J. Recept Res.,13(1-4): 573-90 (1993); and Billard, et al. Life Sciences, 35(18):1885-93 (1984), with modifications

Dopamine, D₁ (human recombinant) binding assay was performed accordingto published procedures. See, e.g., Jarvie, et al. J. Recept Res.,13(1-4): 573-90 (1993); and Gundlach, et al. Life Sciences, 35(19):1981-8 (1984) with modifications.

In vitro binding assays are used to determine 5HT_(2a) binding. Thesebinding assays measure the ability of benzisoxazole analogs to displaceknown standards from the 5HT_(2a), 5HT_(2b), 5HT_(2c), and 5HT7. Adecrease in the binding of the compounds to the M1-M3 receptors,relative to the binding of the compound to the 5HT_(2a) receptor, is anindication of the greater specificity of the compound for the 5HT_(2a)receptor over the muscarinic receptor. Moreover, a drug with increasedspecificity for the 5HT_(2a) receptor possesses less anti-cholinergicside effects. 5HT_(2a) binding is determined as described for example inBritish Journal of Pharmacology (1995) 115, 622-628.

Binding to H1 can be an indication of the desired sleep-inducingactivity of the compound. Binding to muscarinic receptors showsnon-specific binding, and can indicate anti-cholinergic activity whichcan result in undesired side effects, e.g., the side effects of manyknown antihistamines, e.g., blurred vision, dry mouth, constipation,urinary problems, dizziness, anxiety, and the like. A decrease in thebinding of the compounds to the M1-M3 receptors, relative the binding ofthe compound to the H1 receptor, is an indication of the greaterspecificity of the compound for the histamine receptor over themuscarinic receptor. Moreover, a drug with increased specificity for thehistamine receptor would possess less anti-cholinergic side effects.

In addition to the in vitro selection criteria described above,olanzapine analogs of the invention are selected using the following invivo sleep-wake and physiological assessments:

NonREM Sleep: Olanzapine analogs are selected if, in adult, male Wistarrats, (i) peak nonREM amount exceeds 55% nonREM per hour by no laterthan the third hour post-treatment; and (ii) the nature of this increasein nonREM sleep is such that the net cumulative total increase in nonREMsleep in the initial 6 hours post-treatment (adjusted for baseline atthe corresponding circadian time 24 hours earlier, and relative toVehicle control treatment) is not less than 20 minutes in total forcompound doses that produces maximum sleep consolidation as measured bysleep bout length, when drug is delivered orally.

The term “nonREM peak sleep time” is defined as an absolute peak amountof nonREM sleep per hour post treatment, with drug administrationoccurring at Circadian Time (CT) 18, which is 6 hours after lights offin a nocturnal laboratory rat when housed in a LD 12:12 (12-hours lightand 12 hours dark) light-dark cycle. The nominal criteria of 55% nonREMsleep per hour is equivalent to 33 minutes of nonREM sleep per hour.

As used herein, the term “cumulative nonREM sleep” is defined as the nettotal aggregate increase in the number of minutes of nonREM sleep,measured through out the entire duration of a drug's soporific effect,which typically, but not always occurs in the first 6 hourspost-treatment, adjusted for the net total aggregate number of minutesof nonREM sleep that occurred during the corresponding non-treatmentbaseline times of day recorded 24 hours earlier, relative to likevehicle control treatment.

As defined herein, the term “sleep bout” refers to a discrete episode ofcontinuous or near continuous sleep, comprised of nonREM sleep, REMsleep, or both nonREM and REM sleep stages, delimited prior and afterthe episode by greater than two contiguous 10 second epochs ofwakefulness. The following non-limiting description illustrates thisconcept: WWWWSSSSWSSSSSSSWWSSSSSSSWWWW, wherein each letter representsthe predominant state of arousal (S=sleep, W=wake) observed each 10seconds. The measured sleep “bout” is 21 ten-second epochs or 3.5minutes in duration.

Sleep Consolidation: Olanzapine analogs are selected if, in adult maleWistar rats, (i) the absolute duration of longest continuous sleepepisodes (i.e., “sleep bout”) post-treatment is greater than 13 minutesin duration; (ii) the net longest sleep bout post treatment is greaterthan or equal to 3 minutes when adjusted for baseline 24 hours earlierand calculated relative to vehicle treatment; and (iii) the meanabsolute duration of every sleep bout when averaged per hour, on an hourby hour basis, is greater than or equal to 5 minutes. The aforementionedselection criteria assume that stages of sleep and wakefulness aredetermined continuously every 10 seconds (e.g., 10 second sleep scoring“epochs”), that sleep and wakefulness are measured polygraphically usingEEG and EMG criteria, and sleep episodes (comprised of nonREM and/or REMsleep) are defined as continuous “bouts” until the episode isinterrupted by greater than two contiguous 10 second epochs ofwakefulness.

As used herein, the term “longest sleep bout length” is defined as thetotal number of minutes an animal remains asleep (nonREM and/or REMsleep stages) during the single longest sleep bout that occurredbeginning in a given hour post-treatment. The “sleep bout length”measurement criteria assumes sleep is measured continuously in 10 secondepochs, and is scored based upon the predominant state, computed orotherwise determined as a discrete sleep stage (where sleep stages aredefined as nonREM sleep, REM sleep, or wakefulness) during the 10 secondinterval that defines the epoch.

The term “average sleep bout length” is defined as the average duration(in minutes) of every and all sleep episodes or bouts that began in agiven hour, independent of the individual duration of each episode orbout.

Concurrently Measured Side Effects: Olanzapine analogs are selected if,in adult, male Wistar rats, these compounds (i) do not produceappreciable amounts of rebound insomnia; (ii) do not appreciably inhibitREM sleep; and (iii) do not disproportionately inhibit locomotor motoractivity and/or motor tone relative to the normal effects of sleepitself. The threshold definitions for these three side-effect variablesare as follows:

“Rebound insomnia” is defined as period of rebound, paradoxical, orcompensatory wakefulness that occurs after the sleep promoting effectsof a hypnotic or soporific agent. Rebound insomnia is typically observedduring the usual circadian rest phase 6-18 hours post-treatment at CT-18(6 hours after lights-off, given LD 12:12), but can occur at any timeduring the initial 30 hours post-treatment. Rebound is consideredunacceptable when, in the adult, male Wistar rat, excess cumulativewakefulness associated with rebound insomnia is greater than 10%reduction in average of hourly NonREM sleep times during post-treatmentcircadian rest phase (lights-on).

In adult, male Wistar rats, rebound insomnia manifests as an increase inwakefulness relative to corresponding times at baseline (24 hoursearlier) subsequent to a drug-induced sleep effect, and rebound insomniais measured cumulatively.

“REM sleep inhibition” is defined as the reduction of REM sleep timepost-treatment at CT-18 (6 hours after lights-off; LD 12:12) or at CT-5(5 hours after lights-on; LD 12:12). Compounds that reduce REM sleeptime by greater than 15 minutes (relative to baseline and adjusted forvehicle treatment) when administered at either CT-18 or CT-5 areconsidered unacceptable.

As defined herein, “disproportionate locomotor activity inhibition” is areduction of locomotor activity that exceeds the normal and expectedreduction in behavioral activity attributable to sleep. Logic dictatesthat if an animal is asleep, there will normally be a correspondingreduction in locomotor activity. If a hypnotic or soporific compoundreduces locomotor activity levels in excess of 20% greater than thatexplained by sleep alone, the compound is deemed unacceptable. Locomotoractivity (LMA) or motor tone may be quantified objectively using anyform of behavioral locomotor activity monitor (non-specific movements,telemetry-based activity monitoring, 3-dimensional movement detectiondevices, wheel running activity, exploratory measures, electromyographicrecording, etc.) so long as it is measured concurrently with objectivesleep-wakefulness measures in the same animal.

In one embodiment, locomotor activity within the animal's cage ismeasured using a biotelemetry device surgically implanted in theanimal's peritoneal cavity; the implantable device and associatedtelemetry receiver detects if and how much animal moves within the cage.Sleep and wakefulness is measured in 10 second epochs simultaneously.Counts of locomotor activity per unit time are divided by the concurrentamount of wakefulness per the same unit, yielding a “locomotor activityintensity” (LMAI) measure for that unit time. Hypnotic or soporificcompounds administered at CT-18 (6 hours after lights-off; LD 12:12)that decrease locomotor activity per unit time awake by greater than 20%relative to vehicle would be judged unacceptable.

In another embodiment, the olanzapine analogs of the invention areselected using the in vivo sleep-wake and physiological assessmentcriteria shown in Table 6:

TABLE 6 Change from baseline value relative to vehicle SCORE-2000Absolute Value only NonREM Peak Time >55% sleep/hour peak Not applicableCumulative NonREM Not applicable >20 minutes at ED100 for MSBL at T₁₋₆Longest Sleep Bout >17 minutes absolute peak >5 minutes Average SleepBout >6 minutes absolute peak Not used in SAR cuts Rebound Insomnia <10%reduction in average of Not applicable hourly NonREM sleep times duringpost-treatment circadian rest phase (lights-on) REM Sleep Inhibition notapplicable not to exceed 15 minutes, Rx at CT5 LMAI not applicable notto exceed 20% LMAI reduction

Methods for evaluating these sleep-wake and physiological assessmentcriteria are described above. The “absolute value” shown in secondcolumn of Table 6 refers to the value as determined for each testcompound, while the “change” value shown in the third column of Table 6reflects an adjusted value in which the absolute value is the differencefrom vehicle, when the vehicle values are adjusted for baseline.

In some embodiments, the longest sleep bout is greater than 13 minutesin duration. In others, it is greater than 17 minutes in duration. Insome embodiments, the net longest sleep bout post treatment is greaterthan or equal to 3 minutes in duration. In others, it is greater than orequal to 6 minutes in duration.

Other in vivo sleep-wake and physiological assessment criteria used toselect olanzapine analogs of the invention include measurement of acutebody temperature and latent body temperature as a change in baselinerelative to vehicle. The acute body temperature change should not exceed−0.50° C., and the latent body temperature change should not exceed+0.50° C. at Time 1-6 hours. The acute body temperature (T₁₋₆) isadjusted for the corresponding baseline measured 24 hours earlier,relative to vehicle (the decrease from vehicle). The latent bodytemperature, measured 7-18 hours post drug treatment (T₇₋₁₈), isadjusted for the corresponding baseline measured 24 hours earlier,relative to vehicle (the decrease from vehicle).

Sleep in mammals can be divided into sleep occurring during periods ofrapid eye movement (REM), accompanied by substantial brain activity, andperiods of non-REM (NREM) sleep, accompanied by decreased brainactivity. Typically, a normal nighttime sleep period is occupiedprimarily by NREM sleep, and thus NREM cumulation can serve as a measureof total sleep cumulation, e.g., significantly decreased NREM can beassociated with insomnia and an accumulation of “sleep debt”, e.g., anaccumulated physiological need for sleep that tends to persist until asufficient amount of additional sleep is accumulated. Thus, an increasein NREM associated with a treatment can indicated the treatment'seffectiveness in treating insomnia.

Sleep quality can be associated with sleep continuity or sleepmaintenance. For example, a subject with sleep apnea wakes up numeroustimes during a sleep period, e.g., the subject has difficultymaintaining continuous sleep. Although such a subject can accumulate atypical nights length of sleep, e.g., 8 hours, the sleep is unrefreshingor non-restorative due to the waking caused by the sleep apnea. Thus, anincrease in the longest uninterrupted sleep bout (LUSB, also known aslongest sleep bout) associated with a treatment can indicate thetreatment's effectiveness in enhancing sleep continuity, and thereforein treating sleep maintenance insomnia.

Sleep-wakefulness, locomotor activity and body temperature are monitoredin male Wistar rats treated with a test compound (i.e., olanzapineanalog) initially at a concentration of 10 mg/kg. Higher and lower dosesare assayed for select compounds (e.g., as high as 45 mg/kg, and as lowas necessary to establish a no-effect dose). Treatments are administeredat CT-18, the peak of the activity dominated period (6 hours afterlights-off), and produced soporific (sleep-inducing) effectscharacterized by increased non-REM sleep time, increased sleepcontinuity, but without evidence of REM sleep inhibition or reboundinsomnia.

Sleep-wakefulness, locomotor activity and body temperature weremonitored in vivo with various compounds of the invention. Adult, maleWistar rats (250 g at time of surgery, Charles River Laboratories,Wilmington Mass.) were anesthetized (2% isoflourane in medical gradeoxygen) and surgically prepared with a cranial implant to permit chronicelectro-encephalogram (EEG) and electromyogram (EMG) recording. Bodytemperature and locomotor activity were monitored via a miniaturetransmitter (Mini-Mitter, Bend, Oreg.) surgically placed in the abdomen.The cranial implant consisted of stainless steel screws (two frontal(+3.2 AP from bregma, ±2.0 ML) and two occipital (−6.9 AP, ±5.5 ML)) forEEG recording. Two Teflon®-coated stainless steel wires were positionedunder the nuchal trapezoid muscles for EMG recording. All leads weresoldered to a miniature connector prior to surgery, and gas sterilizedin ethylene oxide. The implant assembly was affixed to the skull withdental acrylic. A minimum of three weeks was allowed for surgicalrecovery.

Each rat was permanently housed in its own individual recording cagelocated within separate, ventilated compartments of custom-designedstainless steel cabinets. Each cage was enhanced with a filter-top riserand low-torque swivel-commutator. Food and water were available adlibitum. A 24-hr light-dark cycle (12 hours light, 12 hours dark) wasmaintained throughout the study. Animals were undisturbed for at least48 hours before and after treatments.

Sleep and wakefulness were determined using “SCORE-2000™” (Hypnion,Worcester, Mass.)—an internet-based sleep-wake and physiologicalmonitoring system. The system monitored amplified EEG (bandpass 1-30Hz), integrated EMG (bandpass 10-100 Hz), body temperature andnon-specific locomotor activity (LMA) via telemetry, and drinkingactivity, continuously and simultaneously. Arousal states wereclassified on-line as non-REM (NREM) sleep, REM sleep, wake, ortheta-dominated wake every 10 seconds. Total drinking and locomotoractivity counts, and body temperature were quantitiated and recordedeach minute, using EEG feature extraction and pattern-matchingalgorithms. From this data, the longest uninterrupted sleep bout (LUSB)was obtained. The classification algorithm used individually-taughtEEG-arousal-state templates, plus EMG criteria to differentiate REMsleep from theta-dominated wakefulness, plus behavior-dependentcontextual rules (e.g., if the animal was drinking, it is awake).Drinking and locomotor activity intensity (LMA) were recorded every 10seconds, while body temperature was recorded each minute. Locomotoractivity was detected by a telemetry receiver (Mini-Mitter) beneath thecage. Telemetry measures (LMA and body temperature) were not part of thescoring algorithm; thus, sleep-scoring and telemetry data wereindependent measures.

Compounds were administered at CT-18, the peak of the activity-dominatedperiod, sufficient time was allowed to view the time course of thetreatment effect before lights-on (6 hours post-treatment). Compoundswere suspended in sterile 0.25% or 0.5% methylcellulose (1-2 ml/kg).Treatments were administered orally as a bolus.

A parallel group study design was employed. Vehicle controls were drawnfrom a large pool (N>200): a subset of the pooled vehicle controls wasselected, based on computerized matching with the 24-hour pre-treatmentbaseline of the active treatment group.

The results of NREM and LUSB parameters were measured for variouscompounds of the present invention. Results are shown in Tables 7A and7B.

TABLE 7A Properties of Compounds H1 (hr) H1 H1 M1 Alpha H1 Nova- (hr)(hr) H1 M2 1B D1 D2 5HT2a Compound # (rat) screen MDS Cerep bovine M3(h) Alpha 1 Alpha 2 (h) (h) (rat) 46 34 30 44 210 56 >10K 2100 >10K >10K1550 533 14.5 44 >10K >10K 847 >10K 1100 89 139 >10K >10K >10K 6500 92729.5 >10K >10K 90 55.5 70 30 >10K >10K >10K 565 196 10.4 >10K D3 =226 >10K 1 2310 >10K >10K >10K >10K >10K >10K >10K >10K 91 53 60.630.1 >10K 1960 2, 2A, 278 202 13.3 >10K 2C >10K all >10K 92 95.6 11953.5 >10K 2060 2, 2A, 129 2480 60.7 >10K 2C >10K all >10K 93 94 110 6245.2 >10K >10K 2, 2A, 300 107 8.2 >10K 2C >10K all >10K 95 200 A1b970 >10K 96 150 A1b 580 >10K 97 98 99 100 101 102 103 52 104 105

TABLE 7B Properties of Compounds. LONGEST UNINTERRUPTED NREM CUMULATIONCom- SLEEP BOUT (0.3, 1.3, 10, and 30 mg/kg) (3, 10, and 30 mg/kg) pound5HT2a 5HT2a 5HT2b 5HT2c 5HT7 0.3 3 10 30 3 10 30 # (h R) (hctx) (h) (h)(h) mg/kg 1 mg/kg mg/kg mg/kg mg/kg mg/kg mg/kg mg/kg 46 200 639 151 1104080 3.9 ± 11.8 ± 2.7 10.8 ± 3.2 15.5 ± 4.1 38 ± 4 42 ± 5 270 398 >10K1.8 89 1000  5.7 ± 1.8 13.6 ± 2.7  14 ± 7 37 ± 6 90 314 12.3 ± 4.0 19.7± 4.1 37 ± 7 48 ± 8 1 >10K −7.0 ± 2.4 4.1 ± 2.1  6 ± 6 12 ± 5 91 59.110.7 ± 3.2 26 ± 4 92 232  3.1 ± 2.5 5.7 ± 1.8 10 ± 4 27 ± 4 93 −3.0 ±2.8 2.0 ± 1.5 16 ± 6 10 ± 5 94 73 19.9 ± 3.7 47 ± 6 95 28 240 15.8 ± 5.243 ± 5 96 22 100  8.0 ± 2.8 28 ± 5 97 −3.6 ± 2.6  7 ± 3 98 −6.2 ± 2.7 12± 7 99 −2.1 ± 2.2  5 ± 5 100 101  5.9 ± 2.4 51 ± 8 102 103 52  5.9 ± 2.325 ± 5 104 105

EXAMPLE 3 Irwin Screen Side Effects

The Irwin screen can provide useful information on potential sideeffects of compounds on general physiological and behavioural functions.The screen is conducted by administering the test compounds orally in0.25% aqueous methylcellulose using male Wistar rats, a frequently usedspecies in such studies and for which background data are readilyavailable.

The Irwin screen tests for numerous parameters in animals that have beenadministered the test compound. For example, the screen can include:in-cage effects, e.g., dispersion, respiratory rate, locomotor activity,restlessness, fighting, alertness, apathy, and exophthalmus; in-arenaeffects, e.g., transfer arousal, spatial locomotion, ptosis, startle,tail elevation, piloerection, touch escape, positional passivity,catalepsy, tighting reflex, visual placing, grip strength, pinna,corneal, pain response, and wire manoeuvre; parameters observed inhandling, e.g., cyanosis, cutaneous blood flow, hypothermia, body tone,pupil size, light-pupil response, lacrimation, grooming, red staining,salivation, and provoked biting; general scores e.g., fearfulness,irritability, abnormal gait, abnormal body carriage, tremors, twitches,convulsions, bizarre behaviour, writhing, vocalisation, diarrhoea,number of defaecations, number of urinations, moribund, lethality, andabnormalities detected. Further details can be found in Irwin, S;Comprehensive observational assessment: I a. A systematic, quantitativeprocedure for assessing the behavioural and physiological state of themouse. Psychopharmacologia (Berl.) 13: 222-257, 1968, the entireteachings of which are incorporated herein by reference.

Irwin screening of the disclosed sleep-inducing agents are performed byCovance (Princeton, N.J.) according to Irwin, above; Covance StandardOperating Procedure (current revision of SOP PHARM 8.10); relevantregulatory authority guidelines ICH (International Committee forHarmonization) Guideline (Topic S7A; CPMP/ICH/539/00) on SafetyPharmacology Studies for human pharmaceuticals (November 2000); and allprocedures carried out on live animals are subject to the provisions ofUnited Kingdom Law, in particular the Animals (Scientific Procedures)Act, 1986. which obliges all UK laboratories to maintain a local ethicalreview process to ensure that all animal use in the establishment iscarefully considered and justified; that proper account is taken of allpossibilities for reduction, refinement or replacement and that highstandards of accommodation and care are achieved.

All chemicals used are purchased from Colorcon, Ltd, Dartford Kent, UKunless otherwise noted and are of ACS reagent grade purity or higher.All test compound formulations are prepared on the day of dosing byCovance Harrogate Dispensary. The test compounds are formulated in 0.25%aqueous methylcellulose at the highest concentration required. Lowerdoses are obtained by serial dilution of the highest concentration using0.25% aqueous methylcellulose. Dose levels are expressed in terms of theamount of test compound administered without regard to purity or activecontent. All formulations are stored at room temperature (nominally 10to 30° C.) in sealed containers and protected from light.

An adequate number of male Wistar (Crl:WI(Glx/BRL/Han) BR:WH) rats areobtained from Charles River Ltd. (Margate, Kent, United Kingdom). Therats are approximately 5 weeks of age and weigh between 150 and 170 g onarrival. The animals are housed in groups of no more than six inpolypropylene cages (33×15×13 cm) or (45×28×20 cm) with solid floors andGrade 10 woodflakes (Datesand Ltd., Cheshire, United Kingdom) asbedding. The cages are cleaned and dried before use. Aspen chew blocksare placed within the cages as a form of environmental enrichment.Routinely, holding rooms are maintained within acceptable limits fortemperature and relative humidity (nominally 19 to 25° C. and 40% to70%, respectively). These rooms are illuminated by fluorescent light for12 hours out of each 24 hour cycle and designed to receive at least 15fresh air changes per hour. Diet (RM1.(E).SQC. (Special Diets ServicesLtd. Witham, United Kingdom) and water from the mains tap supply areprovided ad libitum (except during handling). These are routinelyanalysed for specific constituents and are not found to contain anybiological or chemical entity which might interfere with the testsystem. On arrival, all animals are examined for ill-health. Animals areacclimatised for a period of at least 5 days. During this time, animalsare identified by their cage labels. A veterinary examination isperformed before the start of any experimental procedures to ensuretheir suitability for the study. Prior to the start of the study,animals are allocated randomly to treatment groups and individuallytail-marked as they come to hand. At the end of the study, the animalsare euthanized.

Each animal receives a single oral administration of vehicle or testarticle, using a constant dose of 1 mg/kg. Individual doses are based onindividual body weights, obtained on the day of dosing.

The Irwin screen parameters above are systematically assessed inaccordance with the relevant controls. In general, drug-induced changes,absent in normal animals, are scored using increasing integers with ‘0’being normal (+/−, present/absent may also be used). Parameters presentin normal animals are scored using an integer that allows for increasesand decreases to be recorded. Detailed observations are performed at 30,60, 90, 180 and 300 minutes post-dose. The animals are kept for a 7-daypost-dose period during which time they are observed daily for grosssigns of toxicity and mortality.

EXAMPLE 4 hERG Side Effects

The cardiac potassium channel, hERG, is responsible for the rapiddelayed rectifier current (IKr) in human ventricles. This channel hasbeen selected for evaluation because inhibition of IKr is the mostcommon cause of undesirable cardiac action potential prolongation bynon-cardiac drugs. Increased action potential duration causesprolongation of the QT interval that has been associated with adangerous ventricular arrhythmia, torsade de pointes (Brown, A M; Rampe,D. (2000). Drug-induced long QT syndrome: is hERG the root of all evil?;and Pharmaceutical News 7, 15-20; Rampe, D; Roy, M L; Dennis, A; Brown,A M. (1997), the entire teachings of which are incorporated herein byreference). hERG channels were expressed in a human embryonic kidney(HEK293) cell line that lacks endogenous IKr. Expression in a mammaliancell line is preferable to transient expression in Xenopus oocytesbecause the latter shows a consistent 10-100 fold lower sensitivity tohERG channel blockers. See also, for example: A mechanism for thepro-arrhythmic effects of cisapride (Propulsid): high affinity blockadeof the human cardiac potassium channel hERG. FEBS Lett. 417, 28-32;Weirich, J; Antoni, H. (1998); Rate-dependence of anti-arrhythmic andpro-arrhythmic properties of class I and class III anti-arrhythmicdrugs. Basic Res Cardiol 93 Suppl 1, 125-132; and Yap, Y G; Camm, A J.(1999); and Arrhythmogenic mechanisms of non-sedating antihistamines.Clin. Exp. Allergy 29 Suppl 3, 174-181. The entire teachings of thepreceding articles are incorporated herein by reference.

The in vitro effects of the disclosed sleep-inducing agents on the hERG(human ether-à-go-go-related gene) channel current (IKr, the rapidlyactivating, delayed rectifier cardiac potassium current) are determinedby ChanTest (Cleveland, Ohio) according to Standard Operating Proceduresof ChanTest.

All chemicals used are purchased e.g., from Sigma (St. Louis, Mo.) andare of ACS reagent grade purity or higher. Stock solutions of testarticles and terfenadine (positive control) are prepared using dimethylsulfoxide (DMSO) and stored frozen. Test article and positive controlconcentrations are prepared by diluting stock solutions into a HEPES(N-[2-hydroxyethyl]piperazine-N′-[2-ethanesulfonic acid])-bufferedphysiological saline (HB-PS) solution (composition in mM): NaCl, 137;KCl, 4.0; CaCl₂, 1.8; MgCl₂, 1; HEPES, 10; Glucose, 10; pH adjusted to7.4 with NaOH (prepared weekly and refrigerated until use). Sinceprevious results have shown that 0.3% DMSO does not affect channelcurrent, all test and control solutions will contain 0.1% DMSO. If thefinal DMSO concentration must be greater than 0.3%, to reach a specifiedtest article concentration, a separate vehicle control test with an n>2is performed at the highest final DMSO concentration. Test and controlsolutions are prepared from stock solutions on a daily basis.

Cells used are human embryonic epithelial kidney cells (HEK293; sourcestrain, American Type Culture Collection, Manassas, Va.; sub-strain,ChanTest, Cleveland, Ohio), transformed with adenovirus 5 DNA andtransfected with hERG cDNA. Stable transfectants are selected bycoexpression with the G418-resistance gene incorporated into theexpression plasmid. Selection pressure is maintained by including G418in the culture medium. Cells are cultured in Dulbecco's Modified EagleMedium/Nutrient Mixture F-12 (D-MEM/F-12) supplemented with 10% fetalbovine serum, 100 U/mL penicillin G sodium, 100 μg/mL streptomycinsulfate and 500 μg/mL G418.

Data acquisition and analyses are performed using the suite of pCLAMPprograms (Axon Instruments, CA). Steady state is a limiting constantrate of change with time (linear time dependence) before and after testarticle application. The decrease in current amplitude upon reachingsteady state is used to calculate the percent block relative to control.

All experiments are performed at room temperature (18° C.-24° C.). Eachcell acts as its own control. One concentration (10 μM) of each testarticle is applied to cells expressing hERG (n≧3, where n=the numbercells). Duration of exposure to each concentration is limited to thetime necessary to reach steady-state block, but no longer than 10minutes. One concentration of the positive control article (60 nMterfenadine) is applied to two cells (n≧2). Cells are transferred to therecording chamber and superfused with HB-PS solution. Pipette solutionfor whole cell recordings are (composition in mM): potassium aspartate,130; MgCl₂, 5; EGTA (ethylene glycol tetraacetate), 5; ATP(adenosinetriphosphate), 4; HEPES, 10; pH adjusted to 7.2 with KOH. Pipettesolution is prepared in batches, aliquoted, stored frozen, and a freshaliquot thawed each day. Patch pipettes are made from glass capillarytubing using a P-97 micropipette puller (Sutter Instruments, CA). Acommercial patch clamp amplifier is used for whole cell recordings.Before digitization, current records are low-pass filtered at one-fifthof the sampling frequency.

Onset and steady state block of hERG current due to test article aremeasured using a pulse pattern with fixed amplitudes (depolarization:+20 mV for 2 s; repolarization: −50 mV for 2 s) repeated at 10 sintervals, from a holding potential of −80 mV. Peak tail current ismeasured during the 2 s step to −50 mV. A steady state is maintained forat least 30 seconds before applying test article or positive control.Peak tail currents are measured until a new steady state was achieved.

Typically, values of about 10% or less are regarded as desirable, valuesfrom about 12% to about 30% can be acceptable if the compound has strongsleep-inducing performance and no other significant side effects; andvalues greater than about 30% are regarded as undesirable.

EXAMPLE 5 Specificity for H1 Histamine Receptors

Binding assays were performed using various compounds of the inventionin competitive binding assays with known standards for the H1 histaminereceptor, and the M1, M2, and M3 muscarinic receptors, alpha 1 and alpha2 receptors, and D1 and D2 receptors.

The histamine H1 assays are described in Chang, et al. Heterogeneity ofHistamine H₁-Receptors: Species Variation in [³H]Mepyramine Binding ofBrain Membranes. Journal of Neurochemistry. 32: 1653-1663 (1979);Martinez-Mir, M. I., Pollard, H., Moreau, J., et al. Three HistamineReceptors (H₁, H₂, and H₃) Visualized in the Brain of Human andNon-Human Primates. Brain Res. 526: 322-327 (1990); Haaksma, E. E. J.,Leurs, R. and Timmerman, H. Histamine Receptors: Subclasses and SpecificLigands. Pharmac. Ther. 47: 73-104 (1990). The muscarinic assays aredescribed in Buckley, N. J., Bonner, T. I., Buckley, C. M., and Brann,M. R. Antagonist Binding Properties of Five Cloned Muscarinic ReceptorsExpressed in CHO-K1 Cells. Mol. Pharmacol. 35: 469-476 (1989). Theassays were performed according to the preceding articles, with thefollowing modifications. Chemical reagents in the following wereobtained from Sigma, St. Louis, Mo.

For the histamine H1 assays, the receptors were obtained from bovinecerebellar membrane tissue, with a B_(max) (receptor number) of 6.2femtomol/mg tissue (wet weight) and a KD (binding affinity) of 1.3 nM. Aradioactive ligand ([³H]pyrilamine (15-25)Ci/mmol), K_(i) 1.9 nM, finalconcentration 2.0 nM) was employed, and 10 μM triprolidine (K_(i) 3.3nM) was employed as a non-specific determinant, reference compound, andpositive control. The receptor and the radioactive ligand were combinedwith the test compound at a range of test compound concentrations fromabout 10⁻¹⁰ to about 10⁻⁶ M, and the mixture was incubated out in 50 mMNa—KPO₄ (pH 7.5) at 25° C. for 60 minutes. The reaction was terminatedby rapid vacuum filtration onto glass fiber filters. Radioactivity fromthe displaced radioactive ligand trapped onto the filters was determinedand compared to control values in order to measure any interactions ofthe test compound with the histamine H1 binding site.

For the muscarinic assays, the receptors were obtained from humanrecombinant receptors expressed in CHO cells (PerkinElmer, Inc.,Wellesley, Mass.). The radioactive ligand employed was [³H]-scopolamine,N-methyl chloride (80-100 Ci/mmol). (−)-Methylscopolamine bromide, 1.0μM, was employed as the non-specific determinant, reference compound,and positive control. After incubation, reactions were terminated byrapid vacuum filtration onto glass fiber filters. Radioactivity from thedisplaced radioactive ligand trapped onto the filters was determined andcompared to control values in order to measure any interactions of thetest compound with the respective receptor.

For the M1 receptor assay, the B_(max) (receptor number) was 4.2picomol/mg protein, and the K_(D) (binding affinity) of the receptor was0.05 nM. The radioactive ligand was employed at a final concentration0.5 nM, while the (−)-methylscopolamine bromide had a K_(i) of 0.09 nM.The receptor and the radioactive ligand were combined with the testcompound at a range of test compound concentrations from about 10⁻¹² toabout 10⁻⁵ M, incubated in Dulbecco's Phosphate Buffered Saline (PBS)for 60 minutes at 25° C., and worked up as described above.

For the M2 receptor assay, the B_(max) (receptor number) was 2.1picomol/mg protein, and the K_(D) (binding affinity) of the receptor was0.29 nM. The radioactive ligand was employed at a final concentration0.5 nM, while the (−)-methylscopolamine bromide had a K_(i) of 0.3 nM.The receptor and the radioactive ligand were combined with the testcompound at a range of test compound concentrations from about 10⁻¹² toabout 10⁻⁵ M, incubated in Dulbecco's Phosphate Buffered Saline (PBS)for 60 minutes at 25° C., and worked up as described above.

For the M3 receptor assay, the B_(max) (receptor number) was 4.0picomol/mg protein, and the K_(D) (binding affinity) of the receptor was0.14 nM. The radioactive ligand was employed at a final concentration0.2 nM, while the (−)-methylscopolamine bromide had a K_(i) of 0.3 nM.The receptor and the radioactive ligand were combined with the testcompound at a range of test compound concentrations from about 10⁻¹² toabout 10⁻⁵ M, incubated in 50 mM TRIS-HCl (pH 7.4) containing 10 mMMgCl₂, 1 mM EDTA for 60 minutes at 25° C., and worked up as describedabove.

Adenosine, purinergic A₁ binding assay was performed according topublished procedures. See, e.g., Bruns, et al., Naunyn SchmiedebergsArch. Pharmacol., 335(1): 59-63 (1987), with minor modifications; andFerlany, et al. Drug Dev. Res. 9: 85-93 (1986).

Adenosine, purinergic A₂ binding assay was performed according topublished procedures. See, e.g., Jarvis, et al., J. Pharmacol. Exper.Ther. 251(3): 888-93 (1989) with modifications; and Bruns, et al., Mol.Pharmacol. 29(4): 331-46 (1986) with modifications

Dopamine, D₁ (human recombinant) binding assay was performed accordingto published procedures. See, e.g., Jarvie, et al. J. Recept Res.,13(1-4): 573-90 (1993); and Billard, et al. Life Sciences, 35(18):1885-93 (1984), with modifications

Dopamine, D₁ (human recombinant) binding assay was performed accordingto published procedures. See, e.g., Jarvie, et al. J. Recept Res.,13(1-4): 573-90 (1993); and Gundlach, et al. Life Sciences, 35(19):1981-8 (1984) with modifications

Binding to H1 can be an indication of the desired sleep-inducingactivity of the compound. Binding to muscarinic receptors showsnon-specific binding, and can indicate anti-cholinergic activity whichcan result in undesired side effects, e.g., the side effects of manyknown antihistamines, e.g., blurred vision, dry mouth, constipation,urinary problems, dizziness, anxiety, and the like. A decrease in thebinding of the compounds to the M1-M3 receptors, relative the binding ofthe compound to the H1 receptor, is an indication of the greaterspecificity of the compound for the histamine receptor over themuscarinic receptor. Moreover, a drug with increased specificity for thehistamine receptor would possess less anti-cholinergic side effects.

Table 6A shows the inhibition constant K_(i) in nM for H1 and themuscarinic receptors. It can be seen that Compound 46 is highly specificfor H1 over the muscarinic receptors. Thus, the disclosed compound canbe expected to exhibit good sleep-inducing performance with limited sideeffects associated with muscarinic receptor inhibition.

EXAMPLE 6 Evaluation of Olanzapine Analogs

The following pharmacokinetic parameters are computed from theindividual plasma concentrations of the modified antihistamine compoundusing a noncompartmental approach and appropriate validatedpharmacokinetic software (e.g., WinNonlin Professional). Concentrationvalues reported as BLQ are set to zero. If concentration data areavailable, interim calculations are done (non-QC.d data) between periodsif possible. Dose escalation does not depend on pharmacokineticcalculations.

Descriptive statistics, including mean, standard deviation, coefficientof variation, geometric mean, median, minimum and maximum are computedfor each pharmacokinetic parameter by dose group. Descriptive statisticsfor natural-log transformed AUC(0-t), AUC(0-inf), and Cmax are providedfor each dose level. In addition, mean and median concentration versustime graphs are provided.

Dose proportionality following study medication is explored by analyzingnatural log-transformed pharmacokinetic variables AUC(0-t), AUC(0-inf),and Cmax with a linear model including the natural log-transformed doseas covariates. Dose proportionality is concluded if the 95% confidenceinterval for the slope of the covariate includes the value of 1. Doselinearity for AUC(0-t), AUC(0-inf), and Cmax is also explored by alinear model. See, e.g., Gibaldi and Perrier, Pharmacokinetics, SecondEd., Marcel Dekker: New York, N.Y. (1982). Nominal sample collectiontimes were used in calculations, except where actual sampling times felloutside the protocol-specified acceptable time ranges. The followingparameters are estimated:

-   C_(max) Maximum plasma concentration.-   T_(max) Time to maximum concentration.-   C_(max) and T_(max) were reported directly from the    concentration-time data.-   AUC_(0-t) Area under the plasma concentration-time curve from time 9    to the last time point with measurable concentrations, estimated by    linear trapezoidal rule.-   AUC₀₋₀₀ Area under the plasma concentration-time curve extrapolated    to infinity, calculated using the formula:    AUC₀₋₀₀=AUC₀₋₁+C₀/λ₀

Where C_(t) is the last measurable concentration in plasma and λ_(z) isthe terminal phase elimination rate constant estimated using log-linearregression during the terminal elimination phase. The number of pointsused in λ_(z) calculation was determined by visual inspection of thedata describing the terminal phase. At lest the last three time pointswith measurable values were used in λ_(z) calculation. The number ofpoints used in λ_(z) calculation is based on the best correlation (r₂adjusted) obtained for the time points describing the terminalelimination phase. A r₂ adjusted value for the regression line isconsidered to accurately define the terminal elimination phase if thevalue is >0.7.

-   T_(1/2) Elimination half-life, determined by In(2)λ_(z).-   CL Systemic clearance; for intravenous bolus or infusion, calculated    using the formula:    CL=Dose/AUC₀₋₀₀-    Report CL/F, where F=Absolute bioavailability, for all other routes    of administration.-   V₂ Volume of distribution for all routes of administration,    calculated using the formula:    V_(z)=CLλ_(z)-    CL/F is used to calculate V₂/F for extravascular routes of    administration.

Pharmacokinetic analysis is performed using WinNonlin ProfessionalEdition (Pharsight Corporation, Version 3.3 or 4.1). Descriptivestatistics such as mean and standard deviation are calculated inMicrosoft Excel (Version 8.0e).

Metabolism of test articles in monkey and human cryopreservedhepatocytes was assayed as follows:

TABLE 8 MATERIALS Manufacturer, lot number and exp. Materials DateHepatocytes from Cellzdirect Monkey Human Williams E medium Sigma W1878,exp 2004-11 Foetal calf serum Fisher BW 14-501F, lot 01104637, exp 17Feb 10 0.45 Trypan Blue Biowhittaker 17-942E, lot 01104637, exp Jan 14Test Material Stock Solution CB-1/III/6 DMSO Fisher BP231-100, lot041215, exp 12 Jul 09 10 mM ethoxycoumarin in PSLB 22-A-15, exp Sep. 25,2004 methanol ACN Fisher A998-4, lot 041181, exp June 2007 Formic AcidFisher 032879, exp Mar. 14, 2006Pre-Incubation Preparation:

Sample is diluted with DMSO, to prepare 100 μM and 10 μM stocks. 0.1%formic acid in acetonitrile is prepared by the addition of 1 mL formicacid per 1 L acetonitrile (store RT for 3 months). 10 minute, 60 and 120minute 96 well quenching plates are prepared with 150 μLacetonitrile+0.1% formic acid in each well. Store on ice orrefrigerated.

Next, hepatocytes are thawed and 100 μL of cell suspension is placedinto a microfuge tube with 100 μL 0.4% Trypan Blue solution and gentlymix by inversion. A small amount of the stained cell suspension(approximately 15 μL) is placed into a clean hemacytometer with acoverslip. The hemacytometer is placed onto the stage of the microscopeand the focus and power are adjusted until a single counting squarefills the field. The number of cells in the four outside cornersubdivided squares of the hemacytometer are counted. Viable cells areopalescent, round, and pale with a darker outline. Non-viable cells aredark, opaque blue.

The % viability is calculated as the number of viable cells divided bythe total of cells×100.

The viable cell density and total number of viable cells are calculated:Viable cell Density (D)=Mean 3 of viable cells counted (C)×10^(4×f2);Total number of viable cells (E)=D×26 (resuspension volume). Theadditional media required to achieve a concentration of 1×10⁶ cells/mLis calculated:

${{Volume}\mspace{14mu}{of}\mspace{14mu}{additional}\mspace{14mu}{medium}} = {{\frac{{total}\mspace{14mu}{viable}\mspace{14mu}{cells}}{1 \times 10^{6}}(E)} - {26\mspace{11mu}{mL}}}$

Cells are diluted accordingly and stored at room temperature.

Incubations

198 μL of hepatocytes are transferred to relevant wells on dosing plate.The remaining hepatocyte suspension is combined and place in a suitablecontainer of near boiling water and left for 5 minutes to inactivate thecells (for inactive controls and standard curve preparation).

198 μL of inactive hepatocytes are transferred to control wells and 198μL of blank media are transferred to buffer control wells. Plates arepreincubated for at least 15 min. Reactions are started 2 μL ofappropriate test compound dilution from dosing plate. Plates areincubated in an incubator set at 37° C. for approximately 10 minutes,then 50 μL of incubate is removed to 10 a minute quenching platecontaining 150 μL acetonitrile+0.1% formic acid and stored refrigeratedor on ice. Following 60 minutes, 50 μL of incubate is removed to 60minute quenching plate containing 150 μL acetonitrile+0.1% formic acidand stored refrigerated or on ice. Following 120 minutes, 50 μL ofincubate is removed to 120 minute quenching plate containing 150 μLacetonitrile+0.1% formic acid and stored refrigerated or on ice. Theremaining 50 μL is frozen in incubation plates. Tubes are thencentrifuged at ˜4° C. at ˜1400×g for ˜10 minutes. 100 μL of supernatantis diluted with 100 μL water in analysis plates, plates are storedfrozen at −20° C. prior to analysis.

Preparation of Standard Curves

0.1 μM standard is prepared by the addition of 2 μL of 10 μM dosingsolutions to 198 μL of inactive hepatocytes in standard prep plate. 150μL acetonitrile+0.1% formic acid is added to the standard quenchingplate. 150 μL of 0.1 μM standard is transferred into one column of astandard plate. 75 μL inactive hepatocytes is added to remaining wells.75 μL from 0.1 μM standard is transferred into adjacent well in columnin the plate, and mixed well by titration. Serial dilution is continued.75 μL is removed from final standard (all wells contain 75 μL). Platesare incubated at approximately 37° C. for 10 minutes. 50 μL istransferred into standard quench plate containing 150 μLacetonitrile+0.1% formic acid. Plates are centrifuged along with samplesand dilute supernatant 1:1 with water as above. Samples are storedfrozen at ˜−20° C.

EXAMPLE 7 Clinical Evaluation of Olanzapine Analogs

The goal of a human clinical trial is to collect data on the effects ofolanzapine derivatives. Such data includes, for example, clinical signsand symptoms from physical exam, adverse events, laboratory safety(e.g., hematology, serum clinical chemistry, urinalysis), vital signs(e.g., blood pressure, heart rate, temperature, respiratory rate), andelectrocardiogram (ECG) data.

The clinical trials are conducted as follows:

I. Subject Selection

A minimum of 18 subjects are used (2 enrollment groups of 9 subjectseach). Subject candidates fulfilling the following inclusion criteriaare eligible for participation in the study:

-   -   Healthy adult male subjects, 18-45 years of age.    -   Weighing at least 60 kg and within 15% of their ideal weights        (see Table of Desirable Weights of Adults, Metropolitan Life        Insurance Company, 1983).    -   Medically healthy subjects with clinically insignificant        screening results (e.g., laboratory profiles, medical histories,        ECGS, physical exam).

Subject candidates fulfilling one of the following exclusion criteriaare ineligible for participation in the study:

-   -   History or presence of significant cardiovascular, pulmonary,        hepatic, renal, hematologic, gastrointestinal, endocrine,        immunologic, dermatologic, neurologic, or psychiatric disease.    -   History or presence of sleep disorders.    -   History of chronic or seasonal allergies requiring treatment        with H1 receptor antagonists (i.e., terfenadine, astemizole)        within the 90 days prior to the study.    -   History or presence of alcoholism or drug abuse within the past        2 years.    -   Tobacco or nicotine use within the 90 days prior to the study.    -   Known hypersensitivity or idiosyncratic reaction to the study        drug, possible excipients of the study formulation (Captisol®;        sodium saccharin, F.C.C.; glycerin, U.S.P.; orange flavor;        methylcellulose 400 centipoise, U.S.P.; opurified water), or        related compounds.    -   Donation (standard donation amount or more) of blood or blood        products within 90 days prior to the study.    -   Participation in another clinical trial within 90 days prior to        the first dose.    -   History or presence of any disease, medical condition, or        surgery, which may have an effect on drug absorption,        metabolism, distribution, or excretion.    -   Weight loss or gain (±10%) within 30 days prior to the study.    -   Regular consumption of (e.g., more days than not) excessive        quantities of caffeine-containing beverages (e.g., more than 5        cups of coffee or equivalent per day) within 30 days prior to        the study.    -   Any condition that, in the opinion of the Investigator or        Sponsor makes the subject unsuitable for the study.    -   Use of any prohibited prior or concomitant medications.

Each subject who completes the study screening assessments, meets alleligibility criteria, and is accepted for the study is assigned a uniqueidentification number and receives designated doses of the modifiedantihistamine and placebo according to a randomization scheme. Therandomization scheme is available only to the clinic pharmacy staffpreparing the drug (who are not involved in the administration of thedrug) and is not made available to the subjects, analysts, or members ofthe staff responsible for the monitoring and evaluation of the adverseexperiences.

Subjects may be withdrawn from the study by the Principal Investigatorfor the following reasons:

-   -   Secondary occurrence of a major exclusion criteria.    -   To protect their health.    -   Adverse events.    -   Difficulties in blood collection.    -   To protect the integrity of the study.    -   Protocol violation.    -   Failure to comply with study directions.

The clinical report includes reasons for subject withdrawals as well asdetails relevant to withdrawal. Subjects withdrawn from the trial priorto study completion undergo all procedures scheduled for studycompletion. Subjects withdrawn due to any adverse event (whether seriousor non-serious) or clinically significant abnormal laboratory testvalues are evaluated by the Investigator, or a monitoring physician, andare treated and/or followed up until the symptoms or values return tonormal or acceptable levels, as judged by the Investigator.

II. Study Restrictions

Subjects do not take prescription or over-the-counter medication(including herbal products) during the 7 days preceding the study untilthe final sample of the final pharmacokinetic sampling period has beencollected. Additionally, consumption of foods and beverages containingthe following substances is prohibited as indicated:

-   -   Methylxanthine: 72 hours before each dosing and throughout the        period of sample collection, i.e., caffeine beverages and        equivalents (e.g., chocolate bars) are prohibited.    -   Alcohol: 72 hours before each dosing and throughout the period        of sample collection.

All medications taken during the 30 days prior to study start arerecorded. Any medications taken for chronic or seasonal allergies in the90 days prior to the study is recorded.

Pre-Study Subject Screening: The Informed Consent Form is administeredat screening. Within 14 days prior to dosing, medical history anddemographic data, including name, sex, age, race, body weight (kg),height (cm), alcohol use, and tobacco use are recorded. Each subjectreceives a physical examination including complete vital signs, 12-leadECG, and laboratory tests as specified. The laboratory tests include thefollowing:

-   -   a) Hematology including hemoglobin, MCV, red blood cell count,        hematocrit, MCHC, white blood cell count with differential        platelet count and MCH;    -   b) Serum Chemistry including bun, albumin, ALT (SGOT),        creatinine, alkaline phosphatase, glucose, total bilirubin,        creatine phosphokinase (CPK), sodium, uric acid, AST (SGOT) and        triglycerides;    -   c) Urinalysis including appearance and color, glucose, nitrite,        pH, ketones, urobilinogen, specific gravity, bilirubin,        leukocytes, protein and blood;    -   d) Additional Tests including HIV, urine drug screen, HbsAg,        cannabinoids, HCV, benzodiasepines, HCV, amphetamines, hepatitis        A (IgM), opiates, alcohol, cocaine, and continine.

Subject Management: Subjects are housed from at least 36 hours beforedosing until completion of the 24-hour postdose events. They will returnfor a follow-up visit one week following the final dose or upon earlywithdrawal.

Subjects remain semi-recumbent in bed for the first 4 hours followingdrug administration. However, should adverse events occur at any time,subjects are placed in an appropriate position or are permitted to liedown on their right side. Subjects do not engage in strenuous activityat any time during the confinement period.

Standard meals are provided on Day 1 and Day 2. On Day 1, subjects arerequired to fast for a minimum of 10 hours overnight before dosing andfor at least 4 hours thereafter. However, if the option for a previousdose in the fed state is used in Period 3 of Group 2, a standardhigh-fat meal is given 30 minutes prior to dose. In this case, thehigh-fat breakfast (i.e., approximately 50% of calories from fat)consists of two eggs fried in butter, two strips of bacon, two slices ofbuttered toast, four ounces of hash brown potatoes, and eight ounces ofwhole milk. Foods and beverages containing caffeine or equivalent (e.g.,chocolate bars) are prohibited during confinement.

Water is not permitted from 2 hours before until 2 hours after dosing.Water is allowed at all other times. Standard meals are provided atapproximately 4 and 9 hours after dosing, and at appropriate timesthereafter.

III. Drug Administration

Subjects receive the dose for each period as assigned according to therandomization schedule for dosing sequence for each dose (enrollment)group. Subjects receive the assigned dose in a glass dosing cup, andwithin each dose group, all doses, active and placebo, are administeredat the same volume to maintain the double-blind. Subjects are instructedto swallow the dose.

A total of 240 mL of water is given with dosing. A designated portion ofthe water (assigned by pharmacist based on dosing volume) is added tothe emptied dosing cup, swirled to rinse, and swallowed by the subject.This process is repeated twice and then the remainder of the water isconsumed by the subject.

The starting dose for the first human dose level is based on thetoxicity and safety profiles in the preclinical studies. The equivalentbody surface area conversion from human to rat is ⅙ (ToxicologicalHandbook, Michael J. Dereleko, CRC press, Boca Raton, Fla.). Based onNOAEL of 30 mg/kg/day for rat and body surface equivalent criteria, theequivalent dose in an individual of 60 kg is 300 mg/day (⅙×30 mg/kg/day[rat NOAEL]×60 kg). Based on NOAEL dose in rat (30 mg/kg/day), the doseof 3 mg is approximately 1/10 of the NOAEL dose in rats. The highestdose proposed of 160 mg is also below the NOAEL in rats.

If a dose limiting toxicity (Grade 3 or 4 according to the grade scalemodified from the WHO Common Toxicity Criteria—Appendix I) deemed to berelated to the study medication is observed in any 2 of the 6 subjectsat any dose level, dose escalations are stopped, and the prior dose isconsidered the maximum tolerated dose (MTD).

If one subject at any dose level experiences a dose limiting toxicity,the Principal Investigator (in consultation with the Sponsor) decides,using good clinical judgment, whether to proceed to the next dose levelas planned, or to adjust the next dose level downward from the doseplanned. This consultation is done for all groups following the previousdose group to decide whether to proceed with planned doses or to adjustdoses downward. Additionally, the planned doses may be substituted withintermediate doses if emerging safety or tolerability issues becomeapparent (i.e., there does not have to be a Grade 3 or 4 event) from thepreceding dose that suggests the need to escalate more slowly.

Dose increments is only permitted if, in the opinion of the PrincipalInvestigator, adequate safety and tolerability have been demonstrated atthe previous lower dose. In all cases, the Principal Investigator usesgood clinical judgment to decide whether to adjust the dose or to stopthe study based on an assessment of all factors relevant to the safetyof the subjects.

The Principal Investigator reviews check-in data (e.g., physicalexamination results, vital signs, questionnaire, and clinical laboratoryresults (e.g., serum chemistry, hematology, urinalysis, and urine drugscreen) for clinically significant changes since screening or theprevious period. The Principal Investigator determines if the subjectwill be dosed or withdrawn for the study based on this review.

IV. Clinical Observation

A hematology panel, a serum chemistry panel and a urinalysis isperformed at screening, at each check-in, 24 hours following each dose,and one week following the final dose, or upon early withdrawal. Bloodsamples (approximately 7 mL) are collected from an indwellingintravenous catheter into evacuated glass tubes containing sodiumheparin predose and at 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 10, 12,18, and 24 hours postdose. Urine samples are collected predose andduring the 0-8 hour interval each period. Samples collected during theinterval are not pooled. Each void is considered a sample. The voidingtimes are at will, not scheduled (with the exception of the predose voidand the void at the end of the 8 hour interval).

Vital signs are measured during the screenings. When the time of vitalsigns coincides with an ECG only, the vital signs are taken 10 minutesprior to the ECG. When the time of vital signs coincides with a blooddraw or a blood draw and ECG, the vital signs are taken 10 minutes priorto the blood draw. Respirations and temperature is monitored atcheck-in, 24 hours following each dose, and one week following the finaldose, or upon early withdrawal. Single measurements of blood pressureand heart rate are taken after a minimum of 5 minutes in asemi-recumbent position. Measurements taken during study confinement aremonitored with an AVS machine at check-in; 0 (predose); 0.25, 0.5, 0.75,1, 1.5, 2, 3, 4, 6, 8, 10, 12, 18, and 24 hours postdose; and one weekfollowing the final dose, or upon early withdrawal. For any heart ratemeasurement greater than 100 beats per minute, the heart rate will berechecked two minutes later. On Day 1, at approximately 24 hours priorto dosing, 3 measurements of blood pressure and heart rate, taken 2minutes apart, are taken as described as described above.

A standard 12-lead ECG is performed for each subject at screening, onDay 1 at times coinciding with Day 1 times of 1 hours prior to dose and1, 1.5, 2, 3, 4, and 6 hours postdose; on Day 1 at 1 hour predose and 1,1.5, 2, 3, 4, 6, and 24 hours postdose; and one week following the finaldose or upon early withdrawal. Additional ECGs may be performed at othertimes if deemed necessary. All standard 12-lead ECGs are recorded for 10seconds. Timing and registration technique for ECGs is standardized forall subjects. Subjects should be lying down for at least 1 minute priorto each 12-lead ECG evaluation. The Principal Investigator evaluates PR,QRS, QT, and QTc intervals. When the time of ECGs coincides with a blooddraw, the ECG will be taken following the draw.

A physician examines each subject at screening, each check-in, 24 hoursfollowing each dose, and one week following the final dose, or uponearly withdrawal. Additional examinations are performed at other timesif deemed necessary.

Immediately before vital signs measurements 1 hour predose and at 1, 2,6, and 24 hours postdose (the vital signs are taken 10 minutes prior tothe blood draw designated at these times), subjects are presented avisual analogue scale and asked to draw a vertical mark across a 100 mmline at the point ranging between Very Sleepy and Alert/Wide Awake,which best describes their level of alertness at that time.

The subjects are instructed to inform the study physician or staff ofany adverse events or intercurrent illnesses experienced during thetrial. Additionally, a specific inquiry regarding adverse events isconducted prior to dosing, at 2, 4, 8, and 24 hours postdose, and oneweek following the final dose, or upon early withdrawal. Questions areposed in a non-specific manner so as not to bias the response.

Any subject who has any adverse event (whether serious or non-serious)or clinically significant abnormal laboratory test values is evaluatedby the Investigator, or a monitoring physician, and is treated and/orfollowed up until the symptoms or values return to normal or acceptablelevels, as judged by the Investigator. A physician, either on-site or ata nearby hospital emergency room, administers treatment of any seriousadverse events. Where appropriate, medical tests and examinations areperformed to document resolution of event(s). Outcome is classified as,e.g., resolved, improved, unchanged, worse, fatal, or unknown (lost tofollow-up).

V. Reporting

All adverse events occurring during the clinical trial are recorded.Adverse events are coded using MedDRA (version 4.1). An adverseevent/experience (AE) is any unwarranted medical occurrence in a patientor clinical investigation subject administered a pharmaceutical productthat does not necessarily have a causal relationship with this treatment(ICH/WHO). An adverse event (AE) is, therefore, any unfavorable andunintended sign, (including, for example, an abnormal laboratoryfinding), symptom, or disease temporally associated with the use of amedical product, whether or not considered related to the medicalproduct (ICH/WHO).

The Investigator reviews each event and assesses its relationship todrug treatment (i.e., unrelated, unlikely, possibly, probably, almostcertainly). Each sign or symptom reported is graded on a 3-pointseverity scale (mild, moderate, or severe) and the date and time ofonset, time relationship to drug dosing, duration, and outcome of eachevent is noted. The following definitions for rating severity are used:(1) Mild: The adverse event is easily tolerated and does not interferewith daily activity; (2) Moderate: The adverse event interferes withdaily activity, but the subject is still able to function; (3) Severe:The adverse event is incapacitating and requires medical intervention.

If any of the above adverse events are serious, special procedures arefollowed. All serious adverse events are reported to the Sponsor within24 hours and followed by written reports within 48 hours, whether or notthe serious events are deemed drug-related.

A Serious Adverse Event (SAE) is any untoward medical occurrence that,at any dose, results in death, is life-threatening, results inpermanently disability or incapacitation, requires inpatienthospitalization, prolongs inpatient hospitalization, is a congenitalanomaly, may jeopardize the subject or may require intervention toprevent one or more of the other outcomes listed above.

VI. Pharmacokinetics

The following pharmacokinetic parameters are computed from theindividual plasma concentrations of the modified antihistamine compoundusing a noncompartmental approach and appropriate validatedpharmacokinetic software (e.g., WinNonlin Professional). Concentrationvalues reported as BLQ are set to zero. If concentration data areavailable, interim calculations are done (non-QC.d data) between periodsif possible. Dose escalation does not depend on pharmacokineticcalculations.

Descriptive statistics, including mean, standard deviation, coefficientof variation, geometric mean, median, minimum and maximum are computedfor each pharmacokinetic parameter by dose group. Descriptive statisticsfor natural-log transformed AUC(0-t), AUC(0-inf), and Cmax are providedfor each dose level. In addition, mean and median concentration versustime graphs are provided.

Dose proportionality following study medication is explored by analyzingnatural log-transformed pharmacokinetic variables AUC(0-t), AUC(0-inf),and Cmax with a linear model including the natural log-transformed doseas covariates. Dose proportionality is concluded if the 95% confidenceinterval for the slope of the covariate includes the value of 1. Doselinearity for AUC(0-t), AUC(0-inf), and Cmax is also explored by alinear model.

VII. Assessment of Safety

A by-subject treatment-emergent adverse event data listing includingverbatim term, preferred term, treatment, severity, and relationship totreatment is provided.

The number of subjects experiencing adverse events and number of adverseevents is summarized by dose level using frequency counts.

Safety data including laboratory evaluations and vital signs assessmentsis summarized by dose level and time point of collection. Descriptivestatistics are calculated for quantitative safety data and frequencycounts are compiled for classification of qualitative safety data. Inaddition, a mean change from baseline table is provided for vital signsand a shift table describing out of normal range shifts is provided forclinical laboratory results.

ECG results are classified as normal and abnormal and summarized usingfrequency counts by dose group and time point of collection. Descriptivestatistics are calculated for PR, QRS, QT, and QTc intervals.

Changes in physical exams are described in the text of the final report.

Heart rate data are summarized by treatment group and time point usingdescriptive statistics, as will individual change from baseline values.Mean change from baseline results are used to compare active dose groupsto placebo at each time point. Data from six completed subjects per doselevel should provide 80% certainty to detect a difference of 20 beatsper minute. An interim analysis is completed following each period.

VIII. Assessment of Efficacy

VAS sedation scores are summarized by time point of collection for eachdose level using descriptive statistics.

EXAMPLE 8 Preclinical Evaluation of Olanzapine Analogs

Prior to human clinical testing of compounds, pre-clinical testing isperformed. Pre-clinical evaluation includes the following tests:

i. Preclinical Absorption, Distribution, Metabolism and Excretion

The compound is administered to rats, dogs, and cynomolgus monkeys at adose of approximately 3 mg/kg orally and intravenously. Plasma sampleswere collected from all species for pharmacokinetic analysis. The Tmaxand half life (in hours) is measured in the rat, dog, and monkey.Percent protein bound in rat and human plasma is also measured.

The brains are collected from rats after oral administration todetermine brain levels of the parent drug.

Cytochrome P450 inhibition is studied in vitro. In addition, the invitro rate of metabolism in rat, dog, monkey, and human hepatocytecultures is determined for each compound.

ii. Cardiac Effects Focus

The primary toxicological issue studied during the clinical candidateselection phase of the project is QT interval prolongation.Historically, H1 antagonists have been associated with this effect. QTprolongation in rare instances can evolve into life-threatening cardiacarrhythmias. The best in vitro test to predict the likelihood of acompound causing QT prolongation, the hERG binding assay, was the testsystem chosen to study the potential of a compound to produce thiseffect. The human hERG channel, transfected to a stable cell line, isstudied electrophysiologically and the percent inhibition of the channelcurrent is reported.

To determine if a compound can produce any changes in QT interval, thecompound is studied in telemetered Beagle dogs. Dogs are implanted withdevices to continuously monitor ECG and arterial blood pressure. Dogs(groups of 4) are studied in a Latin square cross-over design, with eachdog receiving 3 different doses and a placebo. Two studies are conductedwith doses of 0.3, 1, 3, 10, and 30 mg/kg.

iii. Acute Rat Study

The purpose of this study is to evaluate the toxicity and maximumtolerated dose (MTD) of the test articles when given via oral gavage torats. Male Crl: CD® (SD)IGS BR rats (3/group) are assigned to 5 groups.At initiation of dosing, animals are approximately 7 weeks old with bodyweights ranging from 172 to 206 g. Each group receives either 50, 100,150, 200, or 250 mg/kg of the compound once daily for 5 days. Allsurviving animals are sacrificed on Day 6. Assessment of toxicity isbased on mortality, clinical observations, and body weight data.

iv. Acute Dog Study

The purpose of this study is to evaluate the toxicity and themaximum-tolerated dose (MTD) of the compound when given at escalatingdoses via oral gavage to dogs. Two male purebred Beagles are assigned tothe study. At initiation of dosing, animals are at least 6 months oldwith body weights ranging from 8.0 to 10.9 kg. Dogs receive dosepreparations containing the compound once daily for 5 days in escalatingdoses of 25, 50, or 75 mg/kg.

The dogs are observed at 0.25, 0.5, 0.75, 1.0, 1.5, and 2.0 hours±5minutes and 4, 6, 8, and 24 hours±15 minutes postdose. They are weighedon Days 1 and 6.

Electrocardiograms are performed and blood pressures are taken prior todosing and at 1, 4, and 24 hours after the 40 mg/kg dose on Day 5.

Based on the range and severity of the clinical signs observed, the MTDis calculated for the compound.

v. 14-Day Rat Study with Recovery Study

The purpose of this study is to evaluate the toxicity of the compoundwhen administered via oral gavage to rats for at least 14 days and toassess the reversibility, persistence, or delayed occurrence of anyeffects after a recovery period of up to 14 days.

Male and female Crl:CD®(SD)IGS BR rats are assigned to seven groups,four main study groups and three groups for toxicokinetics. Each groupreceives dose preparations containing 0.25% methylcellulose, 400 cps in200 mM acetate buffer, or 10, 30, or 150 mg of test article/kg of bodyweight (mg/kg/day) at a dose volume of 5 mL/kg.

Assessment of toxicity is based on mortality, clinical and ophthalmicobservations, body weights, food consumption, clinical pathology, organweights, and macroscopic and microscopic findings. Blood samples arecollected for toxicokinetic evaluation.

14-Day Dog Study with Recovery Phase

The toxicity and the toxicokinetics of a compound of the invention whenadministered daily via oral gavage (Phase 1) or capsules (Phase 2) todogs for at least 14 days is determined. The reversibility, persistence,or delayed occurrence of observable effects following a 7-day (Phase 1)or 14-day (Phase 2) recovery period is also assessed. Doses of 3, 10,30, and 70 mg/kg/day are studied. All Phase 1 and 2 dogs survived untilscheduled sacrifice.

The above compounds and protocols are useful in the pre-clinicalevaluation of olanzapine compounds of the invention.

EXAMPLE 9 Evaluation of Analgesic Activity

The analgesic activity of a olanzapine analog following oraladministration is analyzed. Analgesic activity is assessed by abdominalspasm tests in the rat and mouse. Analgesic activity is also assessedusing the tail clip test in the mouse, tail flick test in the rat,Randall-Selitto test in the rat and comparisons are made with a vehiclecontrol group. Reference compounds ASA (acetylsalicylic acid) andmorphine are also included for comparison.

The tail clip and tail flick test provide useful information about thecentral analgesic activity of the test article. The Randall-Selitto testprovides information on the compound's ability to modify a hyperalgesicstate and the abdominal spasm test provides information on theperipheral analgesic activity of the test article. The test article isadministered by oral gavage, this being the intended clinical route ofadministration. The dose levels employed are expected to encompass theefficacy dose and provide an adequate safety margin.

Test Article, Reference Compound and Irritant Formulation

All formulations are prepared on each day of dosing. The test article isformulated in 0.25% (w/v) MC at the highest concentration required.Lower doses are obtained by serial dilution of the highest concentrationusing 0.25% (w/v) MC. The reference compound, acetylsalicylic acid, isformulated in 0.25% (w/v) MC at the required concentrations. Brewer'syeast is formulated in water for injection at the requiredconcentration. Acetic acid is diluted with water for injection toprovide the required concentration for administration.

Dose levels will be expressed in terms of the amount of test article Ireference compound/irritant administered without regard to purity oractive content.

Animals

An adequate number of male Crl:CD-I(ICR)BR mice and Wistar rats areobtained from Charles River (UK) Ltd., Margate, Kent. The mice areapproximately 4 weeks of age and weigh between 18 and 22 g on arrival.The rats are approximately 5 weeks of age and weigh between 150 and 170g on arrival. The age and weight of the animals at the start of thestudy is documented in the raw data and final report.

The animals are housed in groups appropriate to the size of caging used,in cages that conform to the Code of Practice for the housing and careof animals used in the Scientific Procedures Act (Home Office AnimalsScientific Procedures Act 1986). Bedding is provided on a weekly basisto each cage by use of clean Aspen wood chips (Dates and Ltd,Manchester, UK). The bedding is analyzed for specific contaminants andthe results retained on file at Covance. The cages are cleaned and driedbefore use. Aspen chew blocks are placed within the cages as a form ofenvironmental enrichment. Routinely, holding rooms are maintained withinacceptable limits for temperature and relative humidity (nominally 19 to25° C. and 40 to 70%, respectively). These rooms are illuminated byfluorescent light for 1.2 hours out of each 24 hour cycle and designedto receive at least 15 fresh air changes per hour.

RM1.(E).SQC., (Special Diets Services Ltd., Witham, UK) and water fromthe mains tap supply will be provided ad libitum, except where specifiedbelow. These are routinely analyzed for specific constituents and arenot known to contain any biological or chemical entity which mightinterfere with the test system. The treatment groups employed for thestudy are as shown in Table 9:

TABLE 9 Treatment Groups. Dose level Group Treatment (mg/kg) conc.(mg/mL) # of animals 1 Vehicle — — 8 2 Olanzapine 3 0.3 8 Analog 3Olanzapine 10 1.0 8 Analog 4 Olanzapine 30 3.0 8 Analog 5 Morphine 10010.0 8

Measurements of pressure is taken from the left and right hind paws ofeach animal immediately prior to administration of vehicle, test articleor reference compound and at 30, 60, 120 and 240 minutes post-oraladministration. The order of the pressure measurements is left pawfollowed by right paw.

Abdominal Spasm Test in the Rat

Each animal receives a single administration of vehicle, test article orreference compound by oral gavage, using a constant dose volume 10mg/kg. Individual dose volumes are based on individual body weightsobtained on the day of dosing. The treatment groups are shown in Table10.

TABLE 10 Treatment Groups. Dose level Group Treatment (mg/kg) Conc,(mg/mL) # of animals 1 Vehicle — — 6 2 Olanzapine 3 0.3 6 Analog 3Olanzapine 10 1.0 6 Analog 4 Olanzapine 30 3.0 6 Analog 5 ASA 100 10.0 6

Forty-five minutes following oral administration each animal receives a1 mL intraperitoneal injection of 1% acetic acid. Animals areimmediately placed into individual observation chambers and the numberof abdominal spasms elicited over the subsequent 25-minute period isrecorded.

Abdominal Spasm Test in the Mouse

Each animal receives a single administration of vehicle, test article orreference compound by oral gavage, using a constant dose volume 10mL/kg. Individual dose volumes are based on individual body weightsobtained on the day of dosing. The treatment groups are shown in Table11.

TABLE 11 Treatment Groups. Dose level Group Treatment (mg/kg) Conc.(mg/mL) # of animals 1 Vehicle — — 6 2 Olanzapine 3 0.3 6 Analog 3Olanzapine 10 1.0 6 Analog 4 Olanzapine 30 3.0 6 Analog 5 ASA 100 10.0 6

Forty-five minutes following oral administration each animal receives a0.25 mL intraperitoneal injection of 0.5% acetic acid. Animals areimmediately placed into individual observation chambers and the numberof abdominal spasms elicited over the subsequent 25-minute period isrecorded.

Terminal Procedures

At the end of each test, the animals are humanely killed by a Schedule Icompound (e.g. exposure to carbon dioxide gas in a rising concentrationfollowed by dislocation of the neck) and discarded without necropsy. Ifan animal showed any sign of serious discomfort during the study it issacrificed immediately and humanely. Any animal found dead or killedprematurely during the study is subjected to a necropsy. A macroscopicexamination is performed, after opening the thoracic and abdominalcavities, by observing the appearance of the tissues in situ. Anyabnormalities are recorded.

OTHER EMBODIMENTS

While the invention has been described in conjunction with the detaileddescription thereof, the foregoing description is intended to illustrateand not limit the scope of the invention, which is defined by the scopeof the appended claims. Other aspects, advantages, and modifications arewithin the scope of the following claims. It will be understood by thoseskilled in the art that various changes in form and details may be madetherein without departing from the scope of the invention encompassed bythe appended claims.

1. A compound of Formula IV:

or a pharmaceutically effective salt thereof, wherein: t is 1, 2, 3, or4; R₂, R₃, R₅, and R₆ are, independently, H, F, Cl, Br, OH, CH₃, CF₃,CH₂CH₃, CH(CH₃)₂, OCH₃, CH₂OCH₃, or CH₂OCH₂CH₃; R₉ and R₁₀ are H, CH₃,or CH₂CH₃ or R₉ and R₁₀ together with the carbon to which they areattached are connected to form a spiro ring of size 3, 4, 5, 6, or 7;and Z is selected from CO₂H, CONHS(O)₂-alkyl, CONHS(O)₂-cycloalkyl,CONHS(O)₂-heteroalkyl, or tetrazole.
 2. The compound of claim 1, whereint is 1 or
 2. 3. The compound of claim 2, wherein Z is COOH and at leastone of R₂, R₃, and R₅, and at least one of R₉-R₁₀ are not hydrogen. 4.The compound of claim 3, wherein R₉ and R₁₀ are methyl; R₆ is hydrogen,methyl, ethyl, isopropyl, or halogen; and R₂, R₃, and R₅ are hydrogen.5. The compound of claim 2, wherein the compound of Formula IV used isformula IVa, IVb, IVc, IVd, or IVe:


6. The compound of claim 2, wherein R₉ and R₁₀ are each methyl.
 7. Thecompound of claim 2, wherein R₉ and R₁₀ and the carbon to which they areattached, are connected to form a spiro cyclopropyl ring.
 8. A compound,wherein the compound is Compound 46:


9. A compound selected from formula

wherein R₂, R₃, R₅, R₆, R₉, R₁₀, t, Size Ring, and Z have values definedin the table below and wherein Size Ring is the size of the ring formedwhen R₉ and R₁₀ together with the carbon to which they are attached areconnected to form a spiro ring of the size 3, 4, 5, 6, or 7; Cmpd R₉,Size # R₂ R₃ R₅ R₆ R₁₀ t Ring ** Z  1 H H H H CH₃ 1 none COOH  2 H H H HCH₃ 1 3 COOH  3 H H H H CH₃ 2 none COOH  4 H H F H CH₃ 1 none COOH  5 HH Cl H CH₃ 1 none COOH  6 H H Cl H CH₃ 2 none COOH  7 H H Cl H CH₃ 1 3COOH  8 H H Br H CH₃ 1 none COOH  9 H H Br H CH₃ 1 3 COOH 10 H H CH₃ HCH₃ 1 none COOH 11 H H CH₃ H CH₃ 2 none COOH 12 H H OCH₃ H CH₃ 1 noneCOOH 13 H H OCH₃ H CH₃ 2 none COOH 14 H H OH H CH₃ 1 none COOH 15 H F HH CH₃ 1 none COOH 16 H F CH₃ H CH₃ 1 none COOH 17 H Br H H CH₃ 1 noneCOOH 18 H Br Br H CH₃ 1 none COOH 19 H CH₃ H H CH₃ 1 none COOH 20 H CH₃CH₃ H CH₃ 1 none COOH 21 H OCH₃ H H CH₃ 1 none COOH 22 H OCH₃ F H CH₃ 1none COOH 23 H OCH₃ OCH₃ H CH₃ 1 none COOH 24 H OH H H CH₃ 1 none COOH25 H OH OH H CH₃ 1 none COOH 26 F H H H CH₃ 1 none COOH 27 F H CH₃ H CH₃1 none COOH 28 Br H H H CH₃ 1 none COOH 29 Br H Br H CH₃ 1 none COOH 30CH₃ H H H CH₃ 1 none COOH 31 CH₃ H CH₃ H CH₃ 1 none COOH 32 OCH₃ H H HCH₃ 1 none COOH 33 OCH₃ H F H CH₃ 1 none COOH 34 OCH₃ H CH₃ H CH₃ 1 noneCOOH 35 OCH₃ H OCH₃ H CH₃ 1 none COOH 36 OCH₃ CH₃ H H CH₃ 1 none COOH 37OH H H H CH₃ 1 none COOH 38 OH H OH H CH₃ 1 none COOH 39 H H H OCH₃ CH₃1 none COOH 40 H H H H CH₃ 1 none CONHSO₂CH₃ 41 H H H H CH₃ 1 nonetetrazole 42 H OCH₃ H OCH₃ CH₃ 1 none COOH 43 H OCH₃ CH₃ H CH₃ 2 noneCOOH 44 H Br H CH₃ CH₃ 1 none COOH 45 H H H Br CH₃ 1 none COOH 46 H H HCH₃ CH₃ 1 none COOH 47 H F Br H CH₃ 1 none COOH 48 H F OCH₃ H CH₃ 1 noneCOOH 49 H Br H Br CH₃ 1 none COOH 50 H Br CH₃ H CH₃ 1 none COOH 51 H BrOCH₃ H CH₃ 1 none COOH 52 H CH₃ H CH₃ CH₃ 1 none COOH 53 H CH₃ F H CH₃ 1none COOH 54 H CH₃ OCH₃ H CH₃ 1 none COOH 55 H OCH₃ H CH₃ CH₃ 1 noneCOOH 56 H OCH₃ CH₃ H CH₃ 1 none COOH 57 CH₃ H Br H CH₃ 1 none COOH 58CH₃ H OCH₃ H CH₃ 1 none COOH 59 H H CH₃ H H 1 none COOH 60 H H CH₃ H H 2none COOH 61 H H OCH₃ H H 1 none COOH 62 H H OCH₃ H H 2 none COOH 63 H HOCH₃ H CH₃ 1 3 COOH 64 H Br Br H CH₃ 2 none COOH 65 H CH₃ Br H CH₃ 1none COOH 66 H OH OH H CH₃ 2 none COOH 67 H OCH₃ H F CH₃ 1 none COOH 68H CH₃ H F CH₃ 1 none COOH 69 H H H F CH₃ 1 none COOH 70 H H OCH₃ H CH₃ 1none tetrazole 71 H H OCH₃ H CH₃ 1 none CONHSO₂CH₃ 72 Br H OCH₃ H CH₃ 1none COOH 73 OH H OCH₃ H CH₃ 1 none COOH 74 H H OCH₃ H H 1 nonetetrazole 75 H H OCH₃ H H 1 none CONHSO₂CH₃ 76 H H OCH₃ H H 2 nonetetrazole 77 H H OCH₃ H H 2 none CONHSO₂CH₃ 78 H H OCH₃ H CH₃ 2 nonetetrazole 79 H H OCH₃ H CH₃ 2 none CONHSO₂CH₃ 80 H H OCH₃ H CH₃ 1 3tetrazole 81 H H OCH₃ H CH₃ 1 3 CONHSO₂CH₃ 82 H H OCH₃ H CH₃ 2 3tetrazole 83 H H OCH₃ H CH₃ 2 3 CONHSO₂CH₃ 84 H H OCH₃ H CH₃ 2 3 COOH 85H OCH₃ F H CH₃ 1 none COOH 86 H Br H OCH₃ CH₃ 1 none COOH 87 H CH₃ HOCH₃ CH₃ none COOH 88 CH₃ H F H CH₃ none COOH 89 H H H CH₃ CH₃ 1 noneC(O)N(Na⁺) SO₂CH₃ 90 H H H Ethyl CH₃ 1 none COOH 91 H H H CH₃ CH₃ 1 3COOH 92 H H H CH₃ H 1 none COOH 93 H H H CH₃ H 2 none COOH 94 H H H Iso-CH₃ 1 none COOH propyl 95 CH₃ H H CH₃ CH₃ 1 none COOH 96 CH₃ H H CH₃ CH₃1 3 COOH 97 CH₃ H H CH₃ H 1 none COOH 98 OCH₃ H H CH₃ CH₃ 1 none COOH 99OCH₃ H H CH₃ CH₃ 1 3 COOH 100 H H H CH₃ H 1 none COOH 101 F H H CH₃ CH₃1 none COOH 102 F H H CH₃ CH₃ 1 3 COOH 103 F H H CH₃ H 1 none COOH 104 HCH₃ H CH₃ CH₃ 1 3 COOH 105 H CH₃ H CH₃ H 1 none COOH.